To see the other types of publications on this topic, follow the link: Lymphoid progenitors.
Journal articles on the topic 'Lymphoid progenitors'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Lymphoid progenitors.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Harly, Christelle, Maggie Cam, Jonathan Kaye, and Avinash Bhandoola. "Development and differentiation of early innate lymphoid progenitors." Journal of Experimental Medicine 215, no. 1 (November 28, 2017): 249–62. http://dx.doi.org/10.1084/jem.20170832.
Full textAbstract:
Early innate lymphoid progenitors (EILPs) have recently been identified in mouse adult bone marrow as a multipotential progenitor population specified toward innate lymphoid cell (ILC) lineages, but their relationship with other described ILC progenitors is still unclear. In this study, we examine the progenitor–successor relationships between EILPs, all-lymphoid progenitors (ALPs), and ILC precursors (ILCps). Functional, bioinformatic, phenotypical, and genetic approaches collectively establish EILPs as an intermediate progenitor between ALPs and ILCps. Our work additionally provides new candidate regulators of ILC development and clearly defines the stage of requirement of transcription factors key for early ILC development.
2
Borikar, Sneha, Vivek Philip, Lauren Kuffler, and Jennifer J. Trowbridge. "Lysine Methyltransferase Kmt5a Restricts Myeloid-Biased Output of Lymphoid-Primed Multipotent Progenitors." Blood 128, no. 22 (December 2, 2016): 1487. http://dx.doi.org/10.1182/blood.v128.22.1487.1487.
Full textAbstract:
Abstract Distinct, lineage-biased subsets of multipotent progenitor cells (MPP) dynamically respond to the demands of the hematopoietic system to replenish mature hematopoietic cells as needed. It currently remains unclear as to whether distinct epigenetic mechanisms regulate lineage-specific expansion and differentiation from MPPs. Focusing on lymphoid-primed multipotent progenitor cells (LMPP/MPP4), we performed a lentiviral shRNA screen of 15 epigenetic factors, selected based on differential expression between myeloid-restricted and lymphoid-restricted progenitors. Following a 48 hour infection with lentiviral shRNA constructs or a non-targeting control, the lineage potential of lymphoid-primed multipotent progenitors was interrogated by myeloid and lymphoid colony forming unit (CFU) assays. From this screen, knockdown of the lysine methyltransferase Kmt5a most dramatically altered lineage output from lymphoid-primed multipotent progenitors through an expansion of myeloid lineage colonies without altering lymphoid colony production. To confirm target specificity, two independent shRNA hairpins targeting distinct locations of the Kmt5a transcript demonstrated that knockdown of Kmt5a (97.1% and 99.5% versus non-targeting control shRNA) increased macrophage colony production by 1.94 and 1.95 fold, respectively (P < 0.01 and P < 0.05, n = 3). Preliminary single cell culture experiments support that the enhanced myeloid lineage output from lymphoid-primed multipotent progenitors occurs at the single-cell level through increased cloning efficiency of myeloid-biased cells. Our results suggest that Kmt5a functions to restrict myeloid lineage output from lymphoid-primed multipotent progenitors. Mechanistically, KMT5A is responsible for monomethylation of histone H4K20 and the methylation of non-histone proteins (ex. p53K376). Our ongoing work aims to distinguish between these histone and non-histone targets to determine the precise mechanisms restricting myeloid lineage output from lymphoid-primed multipotent progenitors. This work has direct implications for a better understanding of the molecular drivers of transient myeloid lineage reprogramming of lymphoid-primed multipotent progenitors during hematopoietic regeneration, age associated myeloid lineage skewing of hematopoiesis, and myeloid malignancies. Disclosures No relevant conflicts of interest to declare.
3
Becker, Amy M., Drew G. Michael, Ansuman T. Satpathy, Roger Sciammas, Harinder Singh, and Deepta Bhattacharya. "IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors." Blood 119, no. 9 (March 1, 2012): 2003–12. http://dx.doi.org/10.1182/blood-2011-06-364976.
Full textAbstract:
Abstract While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8−/− BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8−/− common myeloid progenitors and, unexpectedly, Irf8−/− ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context.
4
Karsunky, Holger, Miriam Merad, Antonio Cozzio, Irving L. Weissman, and Markus G. Manz. "Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-committed Progenitors to Flt3+ Dendritic Cells In Vivo." Journal of Experimental Medicine 198, no. 2 (July 21, 2003): 305–13. http://dx.doi.org/10.1084/jem.20030323.
Full textAbstract:
Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice. The exact developmental stages at which hematopoietic progenitors express Flt3, are responsive to its ligand, and subsequently develop to DCs, are not known. Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3. The receptor is down-regulated once definitive B cell, T cell, and megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable on other steady state hematopoietic cell populations. Upon in vivo Flt3 ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny DCs are expanded, whereas Flt3− downstream progenitors are not, or are only slightly increased. Transplantation of common lymphoid and common myeloid progenitors and subsequent Flt3L injection increases progeny DCs of both precursor populations. These findings provide a definitive map of Flt3 expression in the hematopoietic hierarchy and directly demonstrate that Flt3L can drive DC development along both the lymphoid and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs.
5
Buza-Vidas, Natalija, Petter Woll, Anne Hultquist, Sara Duarte, Michael Lutteropp, Tiphaine Bouriez-Jones, Helen Ferry, Sidinh Luc, and Sten Eirik Waelgaard Jacobsen. "FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells." Blood 118, no. 6 (August 11, 2011): 1544–48. http://dx.doi.org/10.1182/blood-2010-10-316232.
Full textAbstract:
Abstract Lymphoid-primed multipotent progenitors with down-regulated megakaryocyte-erythroid (MkE) potential are restricted to cells with high levels of cell-surface FLT3 expression, whereas HSCs and MkE progenitors lack detectable cell-surface FLT3. These findings are compatible with FLT3 cell-surface expression not being detectable in the fully multipotent stem/progenitor cell compartment in mice. If so, this process could be distinct from human hematopoiesis, in which FLT3 already is expressed in multipotent stem/progenitor cells. The expression pattern of Flt3 (mRNA) and FLT3 (protein) in multipotent progenitors is of considerable relevance for mouse models in which prognostically important Flt3 mutations are expressed under control of the endogenous mouse Flt3 promoter. Herein, we demonstrate that mouse Flt3 expression initiates in fully multipotent progenitors because in addition to lymphoid and granulocyte-monocyte progenitors, FLT3− Mk- and E-restricted downstream progenitors are also highly labeled when Flt3-Cre fate mapping is applied.
6
Sitnicka, Ewa, Natalija Buza-Vidas, Henrik Ahlenius, Corrado M. Cilio, Christos Gekas, Jens M. Nygren, Robert Månsson, et al. "Critical role of FLT3 ligand in IL-7 receptor–independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors." Blood 110, no. 8 (October 15, 2007): 2955–64. http://dx.doi.org/10.1182/blood-2006-10-054726.
Full textAbstract:
Abstract The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)–deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor α (IL-7Rα) signaling. Fl−/−Il-7r−/− mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Rα–independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Rα, in regulation of the earliest lineage-negative (Lin−) Lin−SCA1+KIT+ (LSK) FLT3hi lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
7
Ryan, Daniel H., Bonnie L. Nuccie, Ion Ritterman, Jane L. Liesveld, Camille N. Abboud, and Richard A. Insel. "Expression of Interleukin-7 Receptor by Lineage-Negative Human Bone Marrow Progenitors With Enhanced Lymphoid Proliferative Potential and B-Lineage Differentiation Capacity." Blood 89, no. 3 (February 1, 1997): 929–40. http://dx.doi.org/10.1182/blood.v89.3.929.
Full textAbstract:
Abstract Relatively little is known about the relationship of lymphoid-associated gene expression to the proliferation and differentiation potential of early human bone marrow lymphoid progenitors. Surface expression of interleukin-7 (IL-7) receptor-α (IL-7Rα), a component of the high-affinity receptor for the lymphoid precursor growth factor IL-7, defined a CD34+ progenitor subset lacking the CD19+ pro-B phenotype but demonstrating markedly enhanced lymphoid clonogenic capacity and the ability to differentiate into pro-B cells in short-term culture. These progenitors expressed mRNA for the lymphoid-associated genes Igβ, RAG-1, and PAX-5, and were uniformly TdT-positive (TdT+). In contrast, IL-7Rα−/CD19−/CD34+ progenitors had a 50-fold reduced lymphoid clonogenic capacity and did not differentiate into pro-B cells in short-term culture. Expression of TdT and the lymphoid-associated genes Igβ and RAG-1, but not PAX-5, was detected in this fraction, although at lower levels than in the IL-7Rα+ progenitors. In contrast to IL-7Rα, loss of the stem cell factor receptor c-kit was associated with enhanced lymphoid clonogenic potential and increased B-lineage differentiation potential. These results indicate that IL-7Rα expression defines entry into a developmental stage characterized by upregulation of multiple lymphoid-associated genes and enhanced fitness for B-lymphoid differentiation. The onset of IL-7Rα and PAX-5 expression immediately before acquisition of CD19 is consistent with evidence suggesting upregulation of CD19 through pathways involving PAX-5 and IL-7.
8
Arinobu, Yojiro, Shin-ichi Mizuno, Hirokazu Shigematsu, Hidetoshi Ozawa, Yong Chong, Hiromi Iwasaki, Philippe Kastner, Susan Chan, and Koichi Akashi. "Delineation of the Common Developmental Pathway for Granulocyte/Monocyte and Lymphoid Lineages by Using an Expression Reporter for PU.1." Blood 108, no. 11 (November 16, 2006): 1656. http://dx.doi.org/10.1182/blood.v108.11.1656.1656.
Full textAbstract:
Abstract Understanding how multipotent cells commit to each of their terminal fate potentials is an important aspect of stem cell biology. Hematopoietic stem cells (HSCs) of Lin −Sca-1+c-Kit+ (LSK) phenotype have been purified, which were further divided into CD34-long-term and CD34+ short-term (ST)-HSCs. The existence of phenotypically isolatable common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) downstream of ST-HSCs suggests that the first commitment step after the HSC stage is the bifurcation of lymphoid vs. myeloid pathway. Recent studies, however, suggest that the loss of MegE potential could be an early event in HSC stage. For example, LSK cells activating RAG-1 or Flt-3 expression retained granulocyte/monocyte (GM) but not megakaryocyte/erythrocyte (MegE) potential together with lymphoid potential, suggesting the existence of common progenitor for GM and lymphoid lineages. Here we report that a fraction of ST-LSK cells expressing high levels of PU.1, a transcription factor necessary for GM and lymphoid development, represents GM/lymphoid bipotent progenitors. In mice harboring knock-in GFP reporter for PU.1, LSK cells were divided into GFP high and GFP low subpopulations. Although PU.1low LSK cells were multipotent, PU.1high LSK cells differentiated only into GM and lymphoid cells in vitro and in vivo. We also found that single PU.1high LSK cells differentiated into GM, T and B cells in vivo. These data formally prove the existence of the third major early progenitor population activating PU.1 at a high level, the granulocyte/monocyte/lymphoid progenitor (GMLP). The existence of prospectively isolatable GMLPs strongly suggests that HSCs sequentially lose MegE then GM potential during their lymphoid commitment.
9
Katsura, Yoshimoto. "Redefinition of lymphoid progenitors." Nature Reviews Immunology 2, no. 2 (February 2002): 127–32. http://dx.doi.org/10.1038/nri721.
Full text
10
Loughran, Stephen J., Federico Comoglio, Fiona K. Hamey, Alice Giustacchini, Youssef Errami, Eleanor Earp, Berthold Göttgens, et al. "Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program." Journal of Experimental Medicine 214, no. 10 (September 12, 2017): 3085–104. http://dx.doi.org/10.1084/jem.20161827.
Full textAbstract:
Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro–B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell–programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation.
11
Hanecak, R., D. C. Zovich, P. K. Pattengale, and H. Fan. "Differentiation in vitro of a leukemia virus-induced B-cell lymphoma into macrophages." Molecular and Cellular Biology 9, no. 5 (May 1989): 2264–68. http://dx.doi.org/10.1128/mcb.9.5.2264.
Full textAbstract:
Cells of the hemopoietic system arise by proliferation and differentiation of progenitor cells. This process begins with multipotential stem cells which can self-renew and also undergo progressive differentiation to progenitor cells committed to particular lineages, ultimately yielding mature blood cells (D. Metcalf and M. A. S. Moore, Haematopoietic Cells, 1971). Early commitment of lymphoid progenitors is generally believed to separate the lymphoid lineage from the myeloid and erythroid lineages, whose progenitors are separated late in differentiation (Metcalf and Moore, 1971). We recently developed a derivative of Moloney murine leukemia virus (M-MuLV) in which the enhancer sequences from simian virus 40 were substituted into the M-MuLV long terminal repeat. This recombinant virus (delta Mo + SV M-MuLV) induces pre-B and B lymphoid leukemia with long latency after inoculation of 2-day-old NIH Swiss mice (R. Hanecak, P. K. Pattengale, and H. Fan, J. Virol. 62:2427-2436, 1988). In this report, we describe the derivation of a permanent, virus-producing cell line with the phenotypic characteristics of mature macrophages from a B-cell-derived lymphoblastic lymphoma induced by delta Mo + SV M-MuLV. Comparison studies of immunoglobulin heavy-chain gene rearrangements and also delta Mo + SV M-MuLV proviral integration sites confirmed that the macrophage cell line was derived from the original B-lymphoblastic lymphoma. Moreover, inoculation of the macrophage cell line into animals resulted in histiocytic sarcomas of the macrophage type, thus reflecting stable conversion of B-lymphoid tumor cells to the macrophage phenotype. These results suggest a closer relationship between lymphoid and myeloid cells than previously believed.
12
Hanecak, R., D. C. Zovich, P. K. Pattengale, and H. Fan. "Differentiation in vitro of a leukemia virus-induced B-cell lymphoma into macrophages." Molecular and Cellular Biology 9, no. 5 (May 1989): 2264–68. http://dx.doi.org/10.1128/mcb.9.5.2264-2268.1989.
Full textAbstract:
Cells of the hemopoietic system arise by proliferation and differentiation of progenitor cells. This process begins with multipotential stem cells which can self-renew and also undergo progressive differentiation to progenitor cells committed to particular lineages, ultimately yielding mature blood cells (D. Metcalf and M. A. S. Moore, Haematopoietic Cells, 1971). Early commitment of lymphoid progenitors is generally believed to separate the lymphoid lineage from the myeloid and erythroid lineages, whose progenitors are separated late in differentiation (Metcalf and Moore, 1971). We recently developed a derivative of Moloney murine leukemia virus (M-MuLV) in which the enhancer sequences from simian virus 40 were substituted into the M-MuLV long terminal repeat. This recombinant virus (delta Mo + SV M-MuLV) induces pre-B and B lymphoid leukemia with long latency after inoculation of 2-day-old NIH Swiss mice (R. Hanecak, P. K. Pattengale, and H. Fan, J. Virol. 62:2427-2436, 1988). In this report, we describe the derivation of a permanent, virus-producing cell line with the phenotypic characteristics of mature macrophages from a B-cell-derived lymphoblastic lymphoma induced by delta Mo + SV M-MuLV. Comparison studies of immunoglobulin heavy-chain gene rearrangements and also delta Mo + SV M-MuLV proviral integration sites confirmed that the macrophage cell line was derived from the original B-lymphoblastic lymphoma. Moreover, inoculation of the macrophage cell line into animals resulted in histiocytic sarcomas of the macrophage type, thus reflecting stable conversion of B-lymphoid tumor cells to the macrophage phenotype. These results suggest a closer relationship between lymphoid and myeloid cells than previously believed.
13
Saxena, Nivedita Shankar, Jing Huang, Yujun Yang, Dullei Min, Carmencita Nicolas, Sumana Shashidhar, Janice (Wes) Brown, and Kenneth I. Weinberg. "Dissection of Complementary Vs Unique Cntributions of Kit, Flt3 and IL-7R Signaling to Lymphohematopoietic Development in Vivo." Blood 124, no. 21 (December 6, 2014): 1572. http://dx.doi.org/10.1182/blood.v124.21.1572.1572.
Full textAbstract:
Abstract Lymphohematopoietic development requires partially complementary cytokine signals mediated by the receptor tyrosine kinases Kit and Flt3, while lymphoid development also depends on the Type I cytokine receptor IL-7R. Common lymphoid progenitors (CLP) and the earliest thymic progenitors (ETP) uniquely express all three receptors. Complicating our understanding of the roles of these three cytokine pathways are synergistic cross-receptor interactions by which the RTK can activate non-cognate Type I cytokine receptors, e.g., IL-7R. To unravel the complex interplay between these three pathways, particularly in lymphopoiesis, we analyzed marrow, thymus and spleen populations in mice with loss of function of each of these pathways, alone or in combination (KitW41/W41 mutant, Flt3L-/-, and IL-7-/- knockouts (KO) so that the respective receptors Kit, Flt3 and IL-7R could be used for phenotypic analyses of progenitor populations). As expected, mice with mutations of Kit, alone or in combination with Flt3L and/or IL-7 KO, showed ~85% loss of both long-term (LT) and short-term (ST) HSC, and numbers of subsequent marrow and thymic progenitor populations (multipotent progenitor (MPP) 2, MPP3, CD62L+ lymphoid primed MPP (LMPP), common myeloid progenitor (CMP), granulocyte-macrophage progenitor (GMP), megakaryocyte-erythroid progenitor (MEP), CLP, ETP) decreased proportionately. The earliest effects of Flt3L loss occurred at the MPP3 stage (~80% loss); surprisingly, the number of myeloid progenitors was increased and CLP decreased. IL-7 KO showed declines in lymphoid committed cells at the LMPP through the CLP and ETP stages. Again unexpectedly, IL-7 loss resulted in increased CMP. Mice deficient for both Kit and Flt3L were viable, had further additive reduction in MPP2 numbers, but showed profound, synergistic reductions in MPP3, LMPP, GMP, CLP, and ETP populations. The combination of IL-7 KO with either KitW41/W41 or Flt3L KO had no effect on the MPP2, but caused additive declines in LMPP and CLP. Mice triply deficient for Kit, Flt3L and IL-7 (“TKO” mice) were also viable, but showed profound (>99%) loss of all lymphoid progenitors (LMPP, CLP and ETP). To account for the downstream effects of the reduced HSC compartment in KitW41/W41 mice, the committed progenitor numbers were normalized to the input HSC numbers in the respective mouse strains. In the absence of Kit signaling, Flt3L and IL-7 loss had ~2-3 log greater effects on lymphopoiesis than myelopoiesis. Consistent with the analyses of numbers of lymphoid vs myeloid progenitors, gene expression analyses of sorted progenitors also showed that in the absence of either Kit and Flt3L, Kit and IL-7, or Kit, Flt3L, and IL-7, MPP3 showed a global shift away from expression of lymphoid developmental pathways and towards myeloid pathways. In addition to expression by CLP and ETP, a subset of MPP3 and LMPP also expressed IL-7R at low levels. These results demonstrate that while Kit has global effects on HSC and their progeny, and Flt3 and IL-7R signals are required only by committed progenitors, 1) Flt3 and IL-7R synergize with and complement Kit in directing lymphoid commitment and/or differentiation of MPP; and 2) that Flt3 and IL-7R signal at the MPP3 or LMPP stages to promote lymphoid development, i.e., earlier than phenotypic CLP. These results can be explained by the co-expression of the RTKs and signaling competent IL-7R in LMPP prior to the phenotypic CLP stage, and the previously described RTK-mediated activation of the IL-7R by non-cognate cross-receptor interactions. Analyses of these complex cytokine interactions may be useful in the elucidation of lymphoid committed progenitor subpopulations and lineage fate decisions among MPP, and the development of therapeutic strategies for expansion of specific progenitor cell populations. Disclosures Brown: Cellerant Therapeutics: Consultancy, Equity Ownership, Patents & Royalties.
14
Purizaca, Jessica, Adriana Contreras-Quiroz, Elisa Dorantes-Acosta, Eduardo Vadillo, Lourdes Arriaga-Pizano, Silvestre Fuentes-Figueroa, Horacio Villagomez-Barragán, et al. "Lymphoid Progenitor Cells from Childhood Acute Lymphoblastic Leukemia Are Functionally Deficient and Express High Levels of the Transcriptional Repressor Gfi-1." Clinical and Developmental Immunology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/349067.
Full textAbstract:
Acute lymphoblastic leukemia (ALL) is the most frequent malignancy of childhood. Substantial progress on understanding the cell hierarchy within ALL bone marrow (BM) has been recorded in the last few years, suggesting that both primitive cell fractions and committed lymphoid blasts with immature stem cell-like properties contain leukemia-initiating cells. Nevertheless, the biology of the early progenitors that initiate the lymphoid program remains elusive. The aim of the present study was to investigate the ability of lymphoid progenitors from B-cell precursor ALL BM to proliferate and undergo multilineage differentiation. By phenotype analyses,in vitroproliferation assays, and controlled culture systems, the lymphoid differentiation potentials were evaluated in BM primitive populations from B-cell precursor ALL pediatric patients. When compared to their normal counterparts, functional stem and progenitor cell contents were substantially reduced in ALL BM. Moreover, neither B nor NK or dendritic lymphoid-cell populations developed recurrently from highly purified ALL-lymphoid progenitors, and their proliferation and cell cycle status revealed limited proliferative capacity. Interestingly, a number of quiescence-associated transcription factors were elevated, including the transcriptional repressor Gfi-1, which was highly expressed in primitive CD34+cells. Together, our findings reveal major functional defects in the primitive hematopoietic component of ALL BM. A possible contribution of high levels of Gfi-1 expression in the regulation of the stem/progenitor cell biology is suggested.
15
Reimann, Christian, Liliane Liliane Dal-Cortivo, Emmanuelle M. Six, Andrea Schiavo, Marina Cavazzana-Calvo, and Isabelle Andre-Schmutz. "In Vitro Exposure to DL-4 Increases the in Vitro and In Vivo T-Lymphopoietic Potential of CB Derived CD34+ Progenitor Cells." Blood 118, no. 21 (November 18, 2011): 2980. http://dx.doi.org/10.1182/blood.v118.21.2980.2980.
Full textAbstract:
Abstract Abstract 2980 Notchligand-based culture systems such as OP9-DL1 cells induce HSC to engage towards the T-cell developmental program and allow generation of T-lymphoid progenitors in vitro. In vitro generated murine T-lymphoid progenitors accelerated T-cell reconstitution in vivo. In consistency, human T-lymphoid progenitors generated in co-culture with OP9-DL1 cells enhanced thymic repopulation when injected into NOD/SCID/gc−/− mice (NSG). However, positive effects of human T-lymphoid progenitors on peripheral T-cell reconstitution have not been reported yet. Besides, Notchligand-based culture systems, consisting of genetically modified murine cells might raise safety concern for clinical use. It has been described that exposure of CD34+ cells to immobilized DL4 induces the T-cell developmental program even in absence of stromal cell support. Recently, we have made use of this system to generate T-lymphoid progenitors in vitro. In the present study we have further characterized their T-lymphoid potential in vitro and in vivo. Exposure of human CB-derived CD34+ cells to immobilized DL4 allowed generation of CD34+CD7+ and CD34−CD7++CD5+ progenitors displaying a similar phenotype as early thymic progenitors (ETP) and the prethymocytes (pre-T). Within the DL-4 derived ETP- and preT-like progenitors we observed subsequent up regulation of genes involved in T-cell development and silencing of genes implied in B-cell and myeloid differentiation. T-cell commitment of DL-4 progenitors could be further confirmed by early and intermediate rearrangement events within the TCR d/g/b genes. The pattern of gene expression profile and TCR-rearrangement events displayed a pattern similar to what we observed in corresponding intrathymic developmental stages. DL4-progenitors obtained after 7 days of culture displayed a 30-fold increased in vitro T-lymphoid potential as compared to untreated CD34+ CB progenitors. DL4 ETP-like and preT-like progenitors further completed T-cell differentiation in vitro (in OP9DL1 co-culture) faster than native CD34+ CB progenitors. When transferred into NSG, DL4 progenitors obtained after 7 days of culture were able to repopulate the recipients' thymus and to give rise to mature, polyclonal intrathymic and peripheral T-cells. Two months after transfer recipients of DL4 progenitors displayed advanced intrathymic T-cell development as compared to recipients of CD34+ CB cells. Furthermore, peripheral T-cells could be observed in a number of DL-4 progenitor recipients but not in control mice. Our experiments provide further evidence that DL4 allows in vitro induction of T-cell development and generation of early T-lymphoid progenitors in a system devoid of stromal cell support. These progenitors feature phenotypical and molecular characteristics of immature thymic developmental stages. Moreover, they are able to accelerate T-cell development in vitro and when transferred into NSG. This work provides further evidence of the ability of in vitro -generated human T-cell progenitors to accelerate T-cell reconstitution and simultaneously introduces a culture technique that could be rapidly transferred into a clinical setting. Disclosures: No relevant conflicts of interest to declare.
16
Liu, Qingyang, Myung H. Kim, Leon Friesen, and Chang H. Kim. "BATF regulates innate lymphoid cell hematopoiesis and homeostasis." Science Immunology 5, no. 54 (December 4, 2020): eaaz8154. http://dx.doi.org/10.1126/sciimmunol.aaz8154.
Full textAbstract:
Early hematopoietic progenitors undergo sophisticated developmental processes to become committed innate lymphoid cell (ILC) progenitors and ultimately mature ILC subsets in the periphery. Basic leucine zipper ATF-like transcription factor (Batf) plays important roles in lymphocyte biology. We report here that Batf regulates the production of bone marrow ILC progenitors and maintenance of peripheral ILCs. The expression of Batf is induced during ILC development at the α-lymphoid progenitor stage in response to the cytokine IL-7. As a potential mechanism, up-regulated Batf binds and activates transcription of the Nfil3 gene to promote ILC hematopoiesis. Batf is necessary to maintain normal numbers of early and late ILC progenitors in the bone marrow and mature ILC1, ILC2, ILC3, and NK cells in most peripheral tissues. Batf deficiency causes ILC lymphopenia, leading to defective ILC responses to inflammatory cytokines and defective immunity to enteric bacterial infections. Thus, Batf plays critical roles in bone marrow hematopoiesis, peripheral homeostasis, and effector functions of ILCs.
17
Kohno, Kentaro, Hiromi Iwasaki, Tadafumi Iino, Shin-ichi Mizuno, Peter Sicinski, and Koichi Akashi. "Cyclin A2 Plays a Critical Role in Proliferation of Lymphoid Progenitors." Blood 118, no. 21 (November 18, 2011): 914. http://dx.doi.org/10.1182/blood.v118.21.914.914.
Full textAbstract:
Abstract Abstract 914 Cell cycle regulators could be differentially used among self–renewing stem cells, rapidly expanding progenitor cells, and terminally differentiated cells those clonally replicate. Cyclin A is a regulatory subunit for cyclin dependent kinase (Cdk) 1 and Cdk2, and it drives S phase progression as well as transition to G2/M phase in cell cycle. We have previously reported that cyclin A2 is not required for fibroblast replication but it is indispensable in maintenance of self-renewing stem cells, including embryonic stem cells and hematopoietic stem cells (HSCs) (Cell 138 2009). The question is whether cyclin A2 plays a role in proliferation of hematopoietic progenitors downstream of the HSC. Here, we further assessed the requirement of cyclin A2 in non-self-renewing hematopoietic progenitors. Quantitative RT-PCR analysis showed that cyclin A2 was expressed in hematopoietic progenitor cells as well as stem cells, and its expression level is highest in lymphoid-committed progenitor stages of both T and B cell lineages. Thus, in order to test the role of cylin A2 in early lymphopoiesis, we crossed cyclin A2 floxed mice with Rag1-Cre knock-in mice. Because recombination activating gene (RAG)-1 is essential for generation of pre-BCRs and pre-TCRs that are critical for expansion of B and T lymphoid progenitor cells, respectively, we hypothesized that the requirement of Cyclin A2 in early lymphopoiesis can be assessed in this system. As we expected, the Rag1-Cre cyclin A2 floxed/floxed mice were viable, and have normal numbers of HSCs and myeloid progenitors. They, however, displayed severe reduction of mature T and B cell numbers that were only 1/100 - 1/10 of wild-type controls. The number of common lymphoid progenitor was unchanged, but there were severely reduced preB cells in bone marrow and T cell progenitors from CD4-CD8- double negative stage in thymus. Furthermore, cell cycle analysis shows that the Cyclin A2 disrupted progenitors are unable to progress from S to G2/M phase, and in vitro culture clearly showed that those progenitors are unable to proliferate and resulted in apoptosis. These findings clearly demonstrate that cyclin A2 is indispensable not only for self-renewing HSCs, but also for proliferation of T and B cell progenitors. Disclosures: No relevant conflicts of interest to declare.
18
Welner, Robert S., Rosana Pelayo, Yoshinori Nagai, Karla P. Garrett, Todd R. Wuest, Daniel J. Carr, Lisa A. Borghesi, Michael A. Farrar, and Paul W. Kincade. "Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection." Blood 112, no. 9 (November 1, 2008): 3753–61. http://dx.doi.org/10.1182/blood-2008-04-151506.
Full textAbstract:
Abstract Hematopoietic stem and progenitor cells were previously found to express Toll-like receptors (TLRs), suggesting that bacterial/viral products may influence blood cell formation. We now show that common lymphoid progenitors (CLPs) from mice with active HSV-1 infection are biased to dendritic cell (DC) differentiation, and the phenomenon is largely TLR9 dependent. Similarly, CLPs from mice treated with the TLR9 ligand CpG ODN had little ability to generate CD19+ B lineage cells and had augmented competence to generate DCs. TNFα mediates the depletion of late-stage lymphoid progenitors from bone marrow in many inflammatory conditions, but redirection of lymphopoiesis occurred in TNFα−/− mice treated with CpG ODN. Increased numbers of DCs with a lymphoid past were identified in Ig gene recombination substrate reporter mice treated with CpG ODN. TLR9 is highly expressed on lymphoid progenitors, and culture studies revealed that those receptors, rather than inflammatory cytokines, accounted for the production of several types of functional DCs. Common myeloid progenitors are normally a good source of DCs, but this potential was reduced by TLR9 ligation. Thus, alternate differentiation pathways may be used to produce innate effector cells in health and disease.
19
Chicha, Laurie, David Jarrossay, and Markus G. Manz. "Clonal Type I Interferon–producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations." Journal of Experimental Medicine 200, no. 11 (November 22, 2004): 1519–24. http://dx.doi.org/10.1084/jem.20040809.
Full textAbstract:
Because of different cytokine responsiveness, surface receptor, and transcription factor expression, human CD11c− natural type I interferon–producing cells (IPCs) and CD11c+ dendritic cells were thought to derive through lymphoid and myeloid hematopoietic developmental pathways, respectively. To directly test this hypothesis, we used an in vitro assay allowing simultaneous IPC, dendritic cell, and B cell development and we tested lymphoid and myeloid committed hematopoietic progenitor cells for their developmental capacity. Lymphoid and common myeloid and granulocyte/macrophage progenitors were capable of developing into both functional IPCs, expressing gene transcripts thought to be associated with lymphoid lineage development, and into dendritic cells. However, clonal progenitors for both populations were about fivefold more frequent within myeloid committed progenitor cells. Thus, in humans as in mice, natural IPC and dendritic cell development robustly segregates with myeloid differentiation. This would fit with natural interferon type I–producing cell and dendritic cell activity in innate immunity, the evolutionary older arm of the cellular immune system.
20
Greig, Kylie T., Carolyn A. de Graaf, James M. Murphy, Marina R. Carpinelli, Swee Heng Milon Pang, Jon Frampton, Benjamin T. Kile, Douglas J. Hilton, and Stephen L. Nutt. "Critical roles for c-Myb in lymphoid priming and early B-cell development." Blood 115, no. 14 (April 8, 2010): 2796–805. http://dx.doi.org/10.1182/blood-2009-08-239210.
Full textAbstract:
Abstract c-Myb is a transcription factor with functions in many hematopoietic lineages. c-Myb–deficient mice display reduced numbers of B cells; however, it is unknown what role c-Myb plays in B lymphopoiesis because no critical target genes have been identified in the B-cell lineage. We demonstrate that conditional deletion of c-Myb in B-cell progenitors completely abolishes B-cell development. c-Myb is required for lymphoid progenitors to respond to the cytokines interleukin-7 and thymic stromal lymphopoietin; in the absence of sufficient c-Myb activity, mice display a B lymphopenia that closely resembles that observed in interleukin-7 receptor α–deficient animals. Analysis of the multipotent progenitor compartment indicates that c-Myb is also required for up-regulation of multiple lymphoid-associated genes, including Il7r, and for the subsequent development of the common lymphoid progenitor population. These data show that c-Myb plays a critical role in the regulatory pathways governing lymphoid specification and early B-cell differentiation.
21
Ooehara, Jun, Hina Takano, Shin-ichiro Takayanagi, Hiromitsu Nakauchi, and Hideo Ema. "In Vitro Myelo-Lymphoid Colony Formation by Mouse Hematopoietic Stem Cells." Blood 112, no. 11 (November 16, 2008): 3861. http://dx.doi.org/10.1182/blood.v112.11.3861.3861.
Full textAbstract:
Abstract Hematopoietic stem cells (HSCs) clonally differentiate into all myeloid, B-lymphoid, and T-lymphoid lineages. Mouse HSCs are known to form in vitro colonies comprised of morphologically identifiable myeloid cells such as neutrophils, macrophages, erythroblasts, and megakaryocytes. Whether HSCs are able to differentiate along B-and T-lymphoid lineages in such colonies remains obscure. The co-culture systems with stromal cells such as S17, OP9, OP9/Delta cells have been shown to support B- and T-cell development. These systems have been used to identify subclasses of progenitors with lymphoid potentials. However, neither B cells nor T cells have been successfully generated from HSCs in vitro. This is most likely due to the lack of culture conditions which support HSCs to differentiate into a certain stage of lymphoid progenitors. In this study, we attempted to use serum-free single-cell culture to identify cytokines which fill the developmental gap between HSCs and lymphoid progenitors. Here we show that myelo-lymphoid colonies are formed by HSCs in the presence of thrombopoietin (TPO), interleukin (IL)-11, or IL-12 together with stem cell factor (SCF). CD34-negative/low, c-Kit-positive, Sca-1-positive, lineage marker-negative (CD34-KSL) bone marrow cells were individually cultured with a combination of cytokines for 7 days. All cells in each colony were transplanted into each from a group of lethally irradiated mice, along with compromised bone marrow cells. The recipient mice were periodically analyzed after transplantation to detect transient myeloid and lymphoid reconstitution. All myeloid, B-, and T-lymphoid progenitor activities were detected in single colonies formed in the presence of SCF+TPO, SCF+IL-11, SCF+IL-12. Only myeloid progenitor activity was predominantly detected in single colonies formed in the presence of SCF+IL-3, consistent with previous observations in blast colony assays. All these combinations of cytokines support self-renewal in HSCs to varying degrees. We conclude that TPO, IL-11, and IL-12 directly act on HSCs and support them to differentiate into progenitors with lymphoid differentiation potential. Early differentiation pathways in HSCs are likely to be used in common by myeloid and lymphoid lineages and be supported in common by multiple cytokines.
22
Hao, Qian-Lin, Aswathi A. George, Judy Zhu, Lora Barsky, Ewa Zielinska, Xiuli Wang, Mary Price, Shundi Ge, and Gay M. Crooks. "Human intrathymic lineage commitment is marked by differential CD7 expression: identification of CD7− lympho-myeloid thymic progenitors." Blood 111, no. 3 (February 1, 2008): 1318–26. http://dx.doi.org/10.1182/blood-2007-08-106294.
Full textAbstract:
Abstract The identity and lineage potential of the cells that initiate thymopoiesis remain controversial. The goal of these studies was to determine, at a clonal level, the immunophenotype and differentiation pathways of the earliest progenitors in human thymus. Although the majority of human CD34+lin− thymocytes express high levels of CD7, closer analysis reveals that a continuum of CD7 expression exists, and 1% to 2% of progenitors are CD7−. CD34+lin− thymocytes were fractionated by CD7 expression and tested for lineage potential in B-lymphoid, T-lymphoid, and myeloid-erythroid conditions. Progressive restriction in lineage potential correlated with CD7 expression, that is, the CD7hi fraction produced T and NK cells but lacked B and myelo-erythroid potential, the CD7int (CD10+) fraction produced B, T, and NK cells, but lacked myelo-erythroid potential. The CD7− fraction produced all lymphoid and myelo-erythroid lineages and expressed HSC-associated genes. However, CD34+lin−CD7− thymocytes also expressed early T lymphoid genes Tdt, pTα, and IL-7Rα and lacked engraftment capacity, suggesting the signals that direct lymphoid commitment and corresponding loss of HSC function are rapidly initiated on arrival of HSC in the human thymus. Thus, differential levels of CD7 identify the progressive stages of lineage commitment in human thymus, initiated from a primitive CD7− lympho-myeloid thymic progenitor.
23
Amrani, Yacine M., Jonathan Gill, Armine Matevossian, Eric S. Alonzo, Chingwen Yang, Jae-Hung Shieh, Malcolm A. Moore, Christopher Y. Park, Derek B. Sant'Angelo, and Lisa K. Denzin. "The Paf oncogene is essential for hematopoietic stem cell function and development." Journal of Experimental Medicine 208, no. 9 (August 15, 2011): 1757–65. http://dx.doi.org/10.1084/jem.20102170.
Full textAbstract:
Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen–associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cell-intrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In addition, LT-HSCs from Paf−/− mice had increased levels of reactive oxygen species (ROS), failed to maintain quiescence, and were unable to support LT hematopoiesis. The loss of lymphoid progenitors was likely due the increased levels of ROS in LT-HSCs caused by treatment of Paf−/− mice with the anti-oxidant N-acetylcysteine restored lymphoid progenitor numbers to that of Paf+/+ mice. Collectively, our studies identify Paf as a novel and essential regulator of early hematopoiesis.
24
Richie Ehrlich, Lauren I., Thomas Serwold, and Irving L. Weissman. "In vitro assays misrepresent in vivo lineage potentials of murine lymphoid progenitors." Blood 117, no. 9 (March 3, 2011): 2618–24. http://dx.doi.org/10.1182/blood-2010-05-287102.
Full textAbstract:
Abstract The identity of T-cell progenitors that seed the thymus has remained controversial, largely because many studies differ over whether these progenitors retain myeloid potential. Contradictory reports diverge in their use of various in vitro and in vivo assays. To consolidate these discordant findings, we compared the myeloid potential of 2 putative thymus seeding populations, common lymphoid progenitors (CLPs) and multipotent progenitors (MPPs), and the earliest intrathymic progenitor (DN1), using 2 in vitro assays and in vivo readouts. These assays gave contradictory results: CLP and DN1 displayed surprisingly robust myeloid potential on OP9-DL1 in vitro stromal cocultures but displayed little myeloid potential in vivo, as well as in methylcellulose cultures. MPP, on the other hand, displayed robust myeloid potential in all settings. We conclude that stromal cocultures reveal cryptic, but nonphysiologic, myeloid potentials of lymphoid progenitors, providing an explanation for contradictory findings in the field and underscoring the importance of using in vivo assays for the determination of physiologic lineage potentials.
25
Serwold, Thomas, Lauren I. Richie Ehrlich, and Irving L. Weissman. "Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis." Blood 113, no. 4 (January 22, 2009): 807–15. http://dx.doi.org/10.1182/blood-2008-08-173682.
Full textAbstract:
Abstract Ongoing thymopoiesis requires continual seeding from progenitors that reside within the bone marrow (BM), but the identity of the most proximate prethymocytes has remained controversial. Here we take a comprehensive approach to prospectively identify the major source of thymocyte progenitors that reside within the BM and blood, and find that all thymocyte progenitor activity resides within a rare Flk2+CD27+ population. The BM Flk2+CD27+ subset is predominantly composed of common lymphoid progenitors (CLPs) and multipotent progenitors. Of these 2 populations, only CLPs reconstitute thymopoiesis rapidly after intravenous injection. In contrast, multipotent progenitor-derived cells reconstitute the thymus with delayed kinetics only after they have reseeded the BM, self-renewed, and generated CLPs. These results identify CLPs as the major source of thymocyte progenitors within the BM.
26
Simmons, Szandor, Marko Knoll, Christopher Drewell, Ingrid Wolf, Hans-Joachim Mollenkopf, Corinne Bouquet, and Fritz Melchers. "Biphenotypic B-lymphoid/myeloid cells expressing low levels of Pax5: potential targets of BAL development." Blood 120, no. 18 (November 1, 2012): 3688–98. http://dx.doi.org/10.1182/blood-2012-03-414821.
Full textAbstract:
Abstract The expression of Pax5 commits common lymphoid progenitor cells to B-lymphoid lineage differentiation. Little is known of possible variations in the levels of Pax5 expression and their influences on hematopoietic development. We have developed a retroviral transduction system that allows for the study of possible intermediate stages of this commitment by controlling the levels of Pax5 expressed in Pax5-deficient progenitors in vitro and in vivo. Retroviral transduction of Pax5-deficient pro-/pre-B cell lines with a doxycycline-inducible (TetON) form of the human Pax5 (huPax5) gene yielded cell clones that could be induced to different levels of huPax5 expression. Clones inducible to high levels developed B220+/CD19+/IgM+ B cells, while clones with low levels differentiated to B220+/CD19−/CD11b+/Gr-1− B-lymphoid/myeloid biphenotypic cells in vitro and in vivo. Microarray analyses of genes expressed at these lower levels of huPax5 identified C/ebpα, C/ebpδ, Pu.1, Csf1r, Csf2r, and Gata-3 as myeloid-related genes selectively expressed in the pro-/pre-B cells that can develop under myeloid/lymphoid conditions to biphenotypic cells. Therefore, reduced expression of huPax5 during the induction of early lymphoid progenitors to B-lineage–committed cells can fix this cellular development at a stage that has previously been seen during embryonic development and in acute lymphoblastic lymphoma–like biphenotypic acute leukemias.
27
Abdel-Azim, Hisham, Yuhua Zhu, Roger Hollis, Xiuli Wang, Shundi Ge, Qian-Lin Hao, Goar Smbatyan, Donald B. Kohn, Michael Rosol, and Gay M. Crooks. "Expansion of multipotent and lymphoid-committed human progenitors through intracellular dimerization of Mpl." Blood 111, no. 8 (April 15, 2008): 4064–74. http://dx.doi.org/10.1182/blood-2007-08-107466.
Full textAbstract:
AbstractSelf-renewal capacity is rapidly lost during differentiation of hematopoietic stem cells to lineage-committed progenitors. We demonstrate here that regulated intracellular signaling through the cytokine receptor Mpl induces profound expansion of not only multipotent (ie, lymphomyeloid) but also lymphoid-committed human hematopoietic progenitors. A fusion protein containing the intracellular signaling domain of Mpl and a dimerization domain was constitutively expressed in populations enriched in human lymphomyeloid progenitor/stem cells (CD34+CD38−Lin−CD7−) and multilymphoid progenitors (CD34+CD38−Lin−CD7+). Intracellular dimerization of Mpl in target cells was induced by in vitro or in vivo administration of a diffusible synthetic ligand. In vitro, Mpl dimerization produced divisions of clonogenic, multilineage CD34+ cells able to engraft immunodeficient mice. When dimerization was induced in vivo after transplantation of either lymphomyeloid or multilymphoid progenitors, donor-derived hematopoiesis was sustained for at least 12 weeks and primitive CD34+Lin− progenitors were expanded more than 1000-fold. Lineage potential of progenitors was not altered and differentiation was not prevented by synthetically induced Mpl signaling. These data demonstrate that dimerization of a single cytokine receptor can deliver a profound expansion signal in both uncommitted and lymphoid-committed human hematopoietic progenitors.
28
So, Chi Wai, Holger Karsunky, Piu Wong, Irving L. Weissman, and Michael L. Cleary. "Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9." Blood 103, no. 8 (April 15, 2004): 3192–99. http://dx.doi.org/10.1182/blood-2003-10-3722.
Full textAbstract:
Abstract Differential expression of Hox genes is associated with normal hematopoiesis, whereas inappropriate maintenance of Hox gene expression, particularly Hoxa7 and Hoxa9, is a feature of leukemias harboring mixed-lineage leukemia (MLL) mutations. To understand the pathogenic roles of Hox genes in MLL leukemias, we assessed the impact of Hoxa7 or Hoxa9 nullizygosity on hematopoietic progenitor compartments and their susceptibility to MLL-induced leukemias. Selective reductions in the absolute numbers of committed progenitors, but not of hematopoietic stem cells, distinguished Hoxa7- and Hoxa9-deficient mice. Megakaryocytic/erythroid progenitor (MEP) reductions in Hoxa7-/-mice correlated with reticulocytosis and thrombocytopenia without anemia. Conversely, Hoxa9-/- mice displayed marked lymphopenia and substantial reductions of common lymphoid progenitors (CLPs) and lymphoid precursors, in addition to significant reductions of common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs). In retroviral transduction/transplantation assays, Hoxa7- and Hoxa9-deficient progenitors remained susceptible to transformation by MLL-GAS7, which activates MLL through a dimerization-dependent mechanism. However, Hoxa7-/- or Hoxa9-/-progenitors were less efficient in generating transformed blast colony-forming units (CFUs) in vitro and induced leukemias with longer disease latencies, reduced penetrance, and less mature phenotypes. Thus, Hoxa7 and Hoxa9 contribute to hematopoietic progenitor homeostasis but are not necessary for MLL-GAS7–mediated leukemogenesis, yet they appear to affect disease latency, penetrance, and phenotypes consistent with their critical roles as downstream targets of MLL fusion proteins. (Blood. 2004;103:3192-3199)
29
Prohaska, Susan S., David C. Scherer, Irving L. Weissman, and Motonari Kondo. "Developmental plasticity of lymphoid progenitors." Seminars in Immunology 14, no. 6 (December 2002): 377–84. http://dx.doi.org/10.1016/s1044532302000726.
Full text
30
Six, Emmanuelle, Delphine Bonhomme, Kheira Beldjord, Monika Jurkowska, Liliane Dal Cortivo, Marta Monteiro, Alexandrine Garrigue, Alain Fischer, Marina Cavazzana-Calvo, and Isabelle Andre-Schmutz. "Characterization of Post Natal Human Lymphoid Progenitors." Blood 108, no. 11 (November 16, 2006): 1659. http://dx.doi.org/10.1182/blood.v108.11.1659.1659.
Full textAbstract:
Abstract In humans, little is known about post-natal lymphoid progenitors, especially those able to circulate, colonize the thymus and generate T lymphocytes. On the basis of a previous work published by Anne Galy in 1995, we have detected in the human post-natal bone marrow up to 60 yrs of age a population of progenitors characterized by their CD34+Lin-CD10+ phenotype. Their differentiation potential analysed by culture in methylcellulose medium indicated that in contrast with their CD10− counterparts, CD10+ progenitors have lost erythroid and myeloid potential. On the other hand, CD10+ progenitors cultured on MS5 or OP9/hDL1 stroma demonstrated an enriched capacity to generate B, T and NK lymphocytes as compared to CD10− precursors. In limiting dilution assays, the high lymhoid potential of CD10+ population was confirmed, since 1 out 15 of them gave rise to T cells, 1 out 23 to B cells and 1 out 90 to NK cells. Gene expression profile shows that CD10+ cells express both B and T restricted factors, such as RAG, Gata3, Pax 5 and TdT. In addition, recombination at the IgH locus is already going on, with multiple DJ, but also VDJ recombination products detected. More importantly, CD10+ precursors circulate in the peripheral blood and are detected in the thymus where they are part of the most immature thymocytes CD34+CD1a-CD38-. Altogether, our results demonstrate for the first time the existence of a post-natal lymphoid progenitor population with a broad lymphoid potential and the ability to reach the thymus and generate efficiently T cells. On the long term, their full characterization will pave the way for their enrichment and usage in therapy of primary lymphoid immunodeficiencies.
31
Cumano, Ana, Claire Berthault, Cyrille Ramond, Maxime Petit, Rachel Golub, Antonio Bandeira, and Pablo Pereira. "New Molecular Insights into Immune Cell Development." Annual Review of Immunology 37, no. 1 (April 26, 2019): 497–519. http://dx.doi.org/10.1146/annurev-immunol-042718-041319.
Full textAbstract:
During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor–invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.
32
Doulatov, Sergei, Faiyaz Notta, and John E. Dick. "Clonal Analysis of the Human Hematopoietic Hierarchy Reveals An Early Lymphoid Progenitor with Extensive Monocytic Potential." Blood 114, no. 22 (November 20, 2009): 1503. http://dx.doi.org/10.1182/blood.v114.22.1503.1503.
Full textAbstract:
Abstract Abstract 1503 Poster Board I-526 The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. Although the validity of this model in the mouse has recently been questioned, its status in human hematopoiesis is unclear, since little is known concerning lineage potential of human progenitors at the clonal level. We isolated and clonally mapped the developmental potential of each major progenitor class from neonatal cord blood and adult bone marrow providing the first comprehensive analysis of the human hematopoietic hierarchy. Human myeloid commitment follows the classical pattern of lineage restriction, however lymphoid development is initiated by a novel cell type, termed lympho-myeloid progenitor (LMP), which displays extensive monocytic potential. However, this myeloid capacity is lost following B- or T/NK-cell lineage commitment. The myeloid potential of LMPs is sensitive to extrinsic signals and can be directed towards differentiation into dendritic cells (DCs). Thus, human lymphoid development does not follow a rigid model of segregation of myeloid-lymphoid lineages, but proceeds through LMPs. LMPs can be massively expanded and differentiated into mature T-cells and DCs that are functionally indistinguishable from DCs derived from peripheral blood monocytes. The prospective isolation and elucidation of clonal lineage potential of human progenitors provides the basis for novel cellular therapeutics and a powerful means to uncover the cellular and molecular regulators that govern human lineage commitment. Disclosures: Dick: Roche: Research Funding; CSL Ltd: Research Funding.
33
Mende, Ines, Holger Karsunky, Irving L. Weissman, Edgar G. Engleman, and Miriam Merad. "Flk2+ myeloid progenitors are the main source of Langerhans cells." Blood 107, no. 4 (February 15, 2006): 1383–90. http://dx.doi.org/10.1182/blood-2005-05-1878.
Full textAbstract:
Langerhans cells (LCs) are antigen-presenting cells (APCs) residing in the epidermis that play a major role in skin immunity. Our earlier studies showed that when skin is inflamed LCs are replaced by bone marrow-derived progenitor cells, while during steady-state conditions LCs are able to self-renew in the skin. Identification of the LC progenitors in bone marrow would represent a critical step toward identifying the factors that regulate LC generation as well as their trafficking to the skin. To determine LC lineage origin, we reconstituted lethally irradiated CD45.2 mice with rigorously purified lymphoid and myeloid progenitors from CD45.1 congenic mice. Twenty-four hours later, we exposed the mice to UV light to deplete resident LCs and induce their replacement by progenitors. Reconstitution with common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-macrophage progenitors (GMPs), or early thymic progenitors led to LC generation within 2 to 3 weeks. CMPs were at least 20 times more efficient at generating LCs than CLPs. LCs from both lineages were derived almost entirely from fetal liver kinase-2+ (Flk-2+) progenitors, displayed typical dendritic-cell (DC) morphology, and showed long-term persistence in the skin. These results indicate that LCs are derived mainly from myeloid progenitors and are dependent on Flt3-ligand for their development.
34
Luc, Sidinh, Iain C. Macaulay, Natalija Buza-Vidas, Tiphaine Bouriez-Jones, Michael Lutteropp, Petter Woll, Adam J. Mead, et al. "The Earliest Thymic T Cell Progenitors Sustain B Cell and Myeloid Lineage Potentials." Blood 118, no. 21 (November 18, 2011): 2335. http://dx.doi.org/10.1182/blood.v118.21.2335.2335.
Full textAbstract:
Abstract Abstract 2335 The stepwise lineage-commitment from hematopoietic stem cells (HSCs) in the bone marrow (BM) to T-lymphocyte-restricted progenitors in the thymus represents a paradigm for how distinct stages of lineage restriction from a multipotent to a lineage-restricted progenitor require different extrinsic cues. However, the commitment stage at which progenitors migrate from the BM to the thymus remains unclear. Previous studies demonstrated the existence of adult early thymic progenitors (ETPs) restricted to T lymphocyte and granulocyte-monocyte (GM) fates (Bell and Bhandoola, Nature 2008; Wada et al., Nature 2008). The challenge remains to couple this thymic T–GM restricted progenitor to candidate thymus seeding progenitors (TSPs) identified in the BM, such as common lymphoid progenitors, lymphoid-primed multipotent progenitors (LMPPs) and HSCs, which all also possess B cell potential. Using high resolution FACS and sensitive clonal assays, we have identified the most primitive ETPs in the neonatal thymus and demonstrate at the single cell level that rare Lin−CD4−CD8a−CD25−KIThiFLT3hi ETPs possess combined granulocyte-monocyte (GM), T and B lymphocyte but not megakaryocyte-erythroid (MkE) lineage potentials, identical to closely molecularly related thymus-seeding progenitors in the BM. Moreover, global molecular profiling demonstrates that neonatal Lin−CD4−CD8a−CD25−KIThiFLT3hi ETPs cluster closest to multipotent progenitors in the BM, rather than subsequent (DN1 and DN2) progenitor stages in the thymus. Finally, in support of Lin−CD4−CD8a−CD25−KIThiFLT3hi ETPs with combined T, B and GM lineage potentials, being the most multipotent progenitors in the thymus, phenotypic and functional studies demonstrate that the neonatal thymus is not seeded by HSCs or MPPs with MkE potential. These findings establish for the first time a distinct lineage commitment stage for the transition of T-lineage commitment from the BM to the remote thymus. Disclosures: No relevant conflicts of interest to declare.
35
Canque, Bruno, Sandrine Camus, Ali Dalloul, Edmond Kahn, Micaël Yagello, Colette Dezutter-Dambuyant, Daniel Schmitt, Christian Schmitt, and Jean Claude Gluckman. "Characterization of dendritic cell differentiation pathways from cord blood CD34+CD7+CD45RA+hematopoietic progenitor cells." Blood 96, no. 12 (December 1, 2000): 3748–56. http://dx.doi.org/10.1182/blood.v96.12.3748.
Full textAbstract:
Abstract To better characterize human dendritic cells (DCs) that originate from lymphoid progenitors, the authors examined the DC differentiation pathways from a novel CD7+CD45RA+ progenitor population found among cord blood CD34+ cells. Unlike CD7−CD45RA+ and CD7+CD45RA− progenitors, this population displayed high natural killer (NK) cell differentiation capacity when cultured with stem cell factor (SCF), interleukin (IL)-2, IL-7, and IL-15, attesting to its lymphoid potential. In cultures with SCF, Flt3 ligand (FL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α (standard condition), CD7+CD45RA+ progenitors expanded less (37- vs 155-fold) but yielded 2-fold higher CD1a+ DC percentages than CD7−CD45RA+ or CD7+CD45RA− progenitors. As reported for CD34+CD1a− thymocytes, cloning experiments demonstrated that CD7+CD45RA+ cells comprised bipotent NK/DC progenitors. DCs differentiated from CD7−CD45RA+ and CD7+CD45RA+ progenitors differed as to E-cadherin CD123, CD116, and CD127 expression, but none of these was really discriminant. Only CD7+CD45RA+ or thymic progenitors differentiated into Lag+S100+Langerhans cells in the absence of exogenous transforming growth factor (TGF)-β1. Analysis of the DC differentiation pathways showed that CD7+CD45RA+ progenitors generated CD1a+CD14− precursors that were macrophage-colony stimulating factor (M-CSF) resistant and CD1a−CD14+ precursors that readily differentiated into DCs under the standard condition. Accordingly, CD7+CD45RA+ progenitor-derived mature DCs produced 2- to 4-fold more IL-6, IL-12, and TNF-α on CD40 ligation and elicited 3- to 6-fold higher allogeneic T-lymphocyte reactivity than CD7−CD45RA+ progenitor-derived DCs. Altogether, these findings provide evidence that the DCs that differentiate from cord blood CD34+CD7+CD45RA+ progenitors represent an original population for their developmental pathways and function.
36
Canque, Bruno, Sandrine Camus, Ali Dalloul, Edmond Kahn, Micaël Yagello, Colette Dezutter-Dambuyant, Daniel Schmitt, Christian Schmitt, and Jean Claude Gluckman. "Characterization of dendritic cell differentiation pathways from cord blood CD34+CD7+CD45RA+hematopoietic progenitor cells." Blood 96, no. 12 (December 1, 2000): 3748–56. http://dx.doi.org/10.1182/blood.v96.12.3748.h8003748_3748_3756.
Full textAbstract:
To better characterize human dendritic cells (DCs) that originate from lymphoid progenitors, the authors examined the DC differentiation pathways from a novel CD7+CD45RA+ progenitor population found among cord blood CD34+ cells. Unlike CD7−CD45RA+ and CD7+CD45RA− progenitors, this population displayed high natural killer (NK) cell differentiation capacity when cultured with stem cell factor (SCF), interleukin (IL)-2, IL-7, and IL-15, attesting to its lymphoid potential. In cultures with SCF, Flt3 ligand (FL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α (standard condition), CD7+CD45RA+ progenitors expanded less (37- vs 155-fold) but yielded 2-fold higher CD1a+ DC percentages than CD7−CD45RA+ or CD7+CD45RA− progenitors. As reported for CD34+CD1a− thymocytes, cloning experiments demonstrated that CD7+CD45RA+ cells comprised bipotent NK/DC progenitors. DCs differentiated from CD7−CD45RA+ and CD7+CD45RA+ progenitors differed as to E-cadherin CD123, CD116, and CD127 expression, but none of these was really discriminant. Only CD7+CD45RA+ or thymic progenitors differentiated into Lag+S100+Langerhans cells in the absence of exogenous transforming growth factor (TGF)-β1. Analysis of the DC differentiation pathways showed that CD7+CD45RA+ progenitors generated CD1a+CD14− precursors that were macrophage-colony stimulating factor (M-CSF) resistant and CD1a−CD14+ precursors that readily differentiated into DCs under the standard condition. Accordingly, CD7+CD45RA+ progenitor-derived mature DCs produced 2- to 4-fold more IL-6, IL-12, and TNF-α on CD40 ligation and elicited 3- to 6-fold higher allogeneic T-lymphocyte reactivity than CD7−CD45RA+ progenitor-derived DCs. Altogether, these findings provide evidence that the DCs that differentiate from cord blood CD34+CD7+CD45RA+ progenitors represent an original population for their developmental pathways and function.
37
Calés, Carmela, Leticia Pavón, Katarzyna Starowicz, Claudia Pérez, Mónica Bravo, Tomokatsu Ikawa, Haruhiko Koseki, and Miguel Vidal. "Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis." Molecular and Cellular Biology 36, no. 6 (December 28, 2015): 900–912. http://dx.doi.org/10.1128/mcb.00869-15.
Full textAbstract:
Polycomb chromatin modifiers regulate hematopoietic pluripotent stem and progenitor cell self-renewal and expansion. Polycomb complex redundancy and biochemical heterogeneity complicate the unraveling of the functional contributions of distinct components. We have studied the hematopoietic activity of RYBP, a direct interactor and proposed modulator of RING1A/RING1B-dependent histone H2A monoubiquitylation (H2AUb). Using a mouse model to conditionally inactivateRybpin adult hematopoiesis, we have found that RYBP deletion results in a reversion of B-1-to-B-2 B-cell progenitor ratios, i.e., of the innate (predominantly fetal) to acquired (mostly adult) immunity precursors. Increased numbers of B-1 progenitors correlated with a loss of pre-proB cells, the B-2 progenitors. RYBP-deficient stem and progenitor cell populations (LKS) and isolated common lymphoid progenitors (CLP) gave rise to increased numbers of B-1 progenitorsin vitro. Rybpinactivation, however, did not result in changes of global H2AUb and did not interact genetically withRing1AorRing1Bdeletions. These results show that a sustained regulation of the B-1-to-B-2 switch is needed throughout adult life and that RYBP plays an important role in keeping B-2 dominance, most likely independently of its Polycomb affiliation.
38
Harman, Benjamin C., Juli P. Miller, Neda Nikbakht, Rachel Gerstein, and David Allman. "Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors." Blood 108, no. 3 (August 1, 2006): 878–85. http://dx.doi.org/10.1182/blood-2005-11-4545.
Full textAbstract:
Abstract Current models predict that mouse plasmacytoid dendritic cells (PDCs) derive from lymphoid progenitors. However, we show PDCs arise exclusively from common myeloid progenitors (CMPs) characterized by low-level expression of several lymphoid-associated genes, including a RAG2/GFP reporter transgene. This conclusion is supported by both adoptive transfer experiments and an estrogen treatment strategy that led to marked depletion of very early lymphoid progenitors without affecting RAG2/GFP+ CMPs or the developmental kinetics, RAG-mediated recombinase activity, and cytokine production of PDCs. These data suggest that PDCs arise exclusively from early myeloid progenitors and that promiscuous low-level expression of lymphoid-associated genes is a general feature of PDC progenitors among CMPs.
39
Nagaharu, Keiki, Kohshi Ohishi, and Naoyuki Katayama. "Novel Lymphoid Pathway of Human Plasmacytoid and Conventional Dendritic Cells." Blood 134, Supplement_1 (November 13, 2019): 4998. http://dx.doi.org/10.1182/blood-2019-121448.
Full textAbstract:
[Introduction] Dendritic cells (DCs) play a central role in initiation and regulation of immune response. Human plasmacytoid DCs (pDCs) as well as conventional DCs (cDCs) were shown to differentiate from multi-lymphoid progenitors (MLPs) as well as myeloid progenitors via common DC progenitors. However, lymphoid pathway of DCs remained clarified. Here we investigated lymphoid origin of DCs, using a novel co-culture system which supports differentiation of various lineages of lymphoid and DCs (Br J Haematol. 157:674, 2012; J Immunol. 199:2343, 2017). [Methods and Results] CD34+CD38-CD45RA-CD10-CD7- human hematopoietic stem/progenitor cells (HSPCs) and various lymphoid progenitors including CD34+CD38-CD45RA+CD10-CD7-lymphoid-primed multipotent progenitors (LMPPs), CD34+CD38-CD45RA+CD10+ MLPs,and CD34+CD38+CD45RA+CD10+CD7-CD19- (10SPs), generally though as B/NK progenitors, were isolated from cord blood and cocultured with telomerized human stromal cells with SCF, flt3L, TPO, and GM-CSF. After 17 to 21 days, generation of CD45RA+CD19+ proB, CD56+CD3- NK cells, HLA-DR+IL-3RhighCD303+CD304+pDCs, and CD1c+cDCs was assessed. We observed that not only immature HSPCs, LMPPs and MLPs but also 10SPs gave rise to pDC and cDCs in addition to proB, NK cells. 10SPs were found to be subdivided by expression pattern of c-kit and IL-7 receptor (R), and similarly cocultured with stromal cells. pDCs, cDCs, proB, and NK cells were generated from c-kit+IL-7R- fraction, while pDC, cDCs, and proB, but few or no NK cells were generated from c-kit+IL-7R+ fractions. c-kit-IL-7R+ fraction produced a significantly lower number of cells than c-kit+IL-7R+or- fractions and mainly differentiated into proB cells. By single cell assay of 10SPs, progenitors with differentiation potential for pDC, cDC, and/or proB were detected. These data revealed a differentiation pathway of pDCs and cDCs from relatively mature lymphoid progenitors and suggested the presence of DC and B common progenitors. [Summary] The present study uncovered a closed relationship between B-lymphoid and DC differentiation pathway. We are further attempting to delineate their relationship and differentiation process toward pDCs, cDCs, and proB. Disclosures Nagaharu: kyowa hakko kirin: Research Funding; Astellas Pharma: Research Funding; Nippon Shinyaku: Research Funding; Ono Pharmaceutical: Research Funding. Ohishi:kyowa hakko kirin: Research Funding; Nippon Shinyaku: Research Funding; Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding. Katayama:Sysmex: Honoraria; Taisho Toyama Pharma: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Alexion Pharmaceuticals: Honoraria; Chugai: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Ono Pharmaceutical: Research Funding; Novo Nordisk: Honoraria; Shionogi Pharmaceutical: Honoraria; Shire: Honoraria; Novartis: Honoraria; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; kyowa hakko kirin: Honoraria, Research Funding.
40
Traver, David, Toshihiro Miyamoto, Julie Christensen, Junko Iwasaki-Arai, Koichi Akashi, and Irving L. Weissman. "Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets." Blood 98, no. 3 (August 1, 2001): 627–35. http://dx.doi.org/10.1182/blood.v98.3.627.
Full textAbstract:
Abstract Hematopoietic fate maps in the developing mouse embryo remain imprecise. Definitive, adult-type hematopoiesis first appears in the fetal liver, then progresses to the spleen and bone marrow. Clonogenic common lymphoid progenitors and clonogenic common myeloid progenitors (CMPs) in adult mouse bone marrow that give rise to all lymphoid and myeloid lineages, respectively, have recently been identified. Here it is shown that myelopoiesis in the fetal liver similarly proceeds through a CMP equivalent. Fetal liver CMPs give rise to megakaryocyte–erythrocyte-restricted progenitors (MEPs) and granulocyte–monocyte-restricted progenitors (GMPs) that can also be prospectively isolated by cell surface phenotype. MEPs and GMPs generate mutually exclusive cell types in clonogenic colony assays and in transplantation experiments, suggesting that the lineage restriction observed within each progenitor subset is absolute under normal conditions. Purified progenitor populations were used to analyze expression profiles of various hematopoiesis-related genes. Expression patterns closely matched those of the adult counterpart populations. These results suggest that adult hematopoietic hierarchies are determined early in the development of the definitive immune system and suggest that the molecular mechanisms underlying cell fate decisions within the myeloerythroid lineages are conserved from embryo to adult.
41
Su, Ruijun, Terry-Ann Milford, Ineavely Baez, Abby Jones Weldon, Sinisa Dovat, and Kimberly J. Payne. "Expression of the IL-7R Identifies a Human Common Lymphoid Progenitor (CLP) In Cord Blood Lymphopoiesis." Blood 116, no. 21 (November 19, 2010): 1603. http://dx.doi.org/10.1182/blood.v116.21.1603.1603.
Full textAbstract:
Abstract Abstract 1603 Expression of the IL-7 receptor alpha (IL-7R) is a distinguishing feature of common lymphoid progenitors (CLP) in the mouse. Human B cell development has been thought to differ from that in mouse with respect to the requirement for IL-7, and markers other than IL-7R have been used to identify human progenitor populations enriched for CLP activity. Our previous studies show that IL-7 is essential for adult human B lymphopoiesis and critical for B cell production from hematopietic stem cells (HSCs) in umbilical blood (CB) (J Immunol. 2009, 182:4255). Here we use IL-7R expression to identify a human CLP population generated in vitro from HSCs in CB. Following 2 weeks of co-culture on primary human BM stroma supplemented with Flt Ligand (FL), CD34+ cells generate a CD34+CD19–IL-7R+ progenitor population that is not present in fresh CB. These IL-7R+ progenitors make up approximately ∼17% of the CD19–CD34+ cells present in culture at 2 weeks. IL-7R+ progenitors were FACSsorted and evaluated in stromal cell co-cultures for lymphoid potential and in colony forming unit (CFU) assay for myeloid potential. IL-7R+ progenitors gave rise to CD19+ B cells and CD56+ NK cells in liquid cultures, but lacked myeloid potential in CFU assays. We examined the culture-generated CD19–CD34+ progenitors to determine the relationship between the expression of IL-7R and CD10, a marker previously used to identify a CLP-enriched population in BM. We found that CD10+ progenitors comprised a much smaller fraction (∼4%) of CD19–CD34+ cells than IL-7R+ progenitors (17%). Furthermore, the CD10+ progenitors did not entirely overlap the IL-7R+ progenitor population as only about half of CD10+ progenitors expressed the IL-7R. To evaluate B and NK potential of these subsets, culture-generated CD19– CD34+ cells were FACSsorted and further co-cultured with stromal cells and cytokines (FL, IL-7 and IL-15). The IL-7R+ CD10– and the IL-7R+ CD10+ subsets produced substantial populations of B cells (∼20% and 13% of culture progeny, respectively) and NK cells (30% and 14% of culture progeny, respectively). In contrast, the CD10+IL-7R– subset completely lacked B cell potential and showed limited NK differentiation capacity (5% of culture progeny). A comparison of the proliferative capacity of the three progenitor subsets showed that IL-7R+ CD10– cells possessed ∼10 times the proliferative capacity of the other two subsets. Thus, the expression of IL-7R expression, not CD10, is associated with B and NK cell potential and the expression of CD10 is accompanied by a reduction in proliferative capacity. Ongoing experiments will provide data on the T lineage potential of IL-7R+ progenitors and single-cell assessment of B and NK potential, as well as the differentiation of IL-7R progenitors from CB HSCs in the mouse-human xenograft model. Studies described here provide information on lymphoid progenitors that are absent from CB but that can be generated from CB HSCs. This will be important for developing therapies to accelerate and enhance lymphoid reconstitution from HSCs in CB, a hematopoietic source used increasingly for stem cell transplant. Disclosures: No relevant conflicts of interest to declare.
42
Susini, Sandrine, Séverine Mouraud, Elodie Elkaim, Julien Roullier, Sonia Luce, Olivier Pellé, Julie Bruneau, Marina Cavazzana, and Isabelle Andre-Schmutz. "From the Bone Marrow to the Thymic Niche." Blood 124, no. 21 (December 6, 2014): 5123. http://dx.doi.org/10.1182/blood.v124.21.5123.5123.
Full textAbstract:
Abstract To generate T cells throughout adult life, the thymus must import hematopoietic progenitor cells from the bone marrow via the blood. The cellular and molecular mechanisms governing the circulation of thymus-seeding progenitor cells are well characterized in mice but not in humans. The aim of the present study was to characterize the molecular mechanisms and cellular components involved in thymus colonization by lymphoid progenitors (CD34+/CD10+/CD7-/CD24-) and the early steps of thymopoiesis under physiological conditions in humans. Our results demonstrate that circulating lymphoid progenitor cells express CCR9 and CXCR4 chemokine receptors, VLA-4, VLA-5 and VLA-6 integrins and PSGL-1 and CD44 adhesion molecules. We used in vitro migration and adhesion assays to validate the functional status of these markers. As in the mouse, human circulating progenitor cells enter the thymus at the corticomedullary junction (CMJ). Once in the thymus, crosstalk with thymic epithelial cells causes the circulating progenitors to commit to the T-cell differentiation pathway. In order to characterize thymic niches and interactions between circulating progenitors and the thymic stroma, we undertook a chemokine/chemokine-receptor-focused gene expression analysis of sorted lymphoid progenitor cells and CMJ epithelial cells (based on the expression of EpCAM and Delta-like-4). We observed an unexpected gene expression profile for chemokines and chemokine regulators in thymus-seeding CD34+/CD10+/CD7-/CD24- cells and epithelial cells at the CMJ. The present results should help us to highlight candidate genes involved in the early steps of human thymopoiesis. Disclosures No relevant conflicts of interest to declare.
43
Kawano, Yohei, Georg Petkau, Christina Stehle, Pawel Durek, Gitta Anne Heinz, Kousuke Tanimoto, Hajime Karasuyama, Mir-Farzin Mashreghi, Chiara Romagnani, and Fritz Melchers. "Stable lines and clones of long-term proliferating normal, genetically unmodified murine common lymphoid progenitors." Blood 131, no. 18 (May 3, 2018): 2026–35. http://dx.doi.org/10.1182/blood-2017-09-805259.
Full textAbstract:
Key Points We have established a novel culture system for long-term proliferating murine lymphoid progenitors without any genetic manipulation. The cultured lymphoid progenitors can differentiate to lymphoid and myeloid lineages in vitro and in vivo.
44
Hao, Qian-Lin, Judy Zhu, Mary A. Price, Kimberly J. Payne, Lora W. Barsky, and Gay M. Crooks. "Identification of a novel, human multilymphoid progenitor in cord blood." Blood 97, no. 12 (June 15, 2001): 3683–90. http://dx.doi.org/10.1182/blood.v97.12.3683.
Full textAbstract:
The earliest stages of lymphoid commitment from human pluripotent hematopoietic stem cells have not been defined. A clonogenic subpopulation of CD34+CD38− cord blood cells were identified that expressed high levels of the CD7 antigen and possessed only lymphoid potential. CD34+CD38−CD7+ (CD7+) cells uniformly coexpressed CD45RA and HLA-DR;c-kit and Thy-1 expression was absent to low. Clonal analysis demonstrated that single CD7+ cells could generate B cells, natural killer cells, and dendritic cells but were devoid of myeloid or erythroid potential. In contrast, control CD34+CD38−CD7−(CD7−) cells generated both lymphoid and myelo-erythroid cells. The lymphoid potential (generation of lymphoid progeny in bulk and single cell cultures) of CD7+ cells was equivalent to that of the pluripotent CD7− cells. RNA expression studies showed that CD7+ cells expressed PU.1 and GATA-3, but did not express Pax-5, terminal deoxynucleotide transferase, or CD3ε. In contrast to the previously described murine common lymphoid progenitor, the α chain of the receptor for interleukin-7 was not detected by fluorescence-activated cell sorting analysis or RNA polymerase chain reaction in CD7+cells. These studies identify a clonogenic lymphoid progenitor with both B-cell and natural killer cell lineage potential with a molecular profile that suggests a developmental stage more primitive than previously identified lymphoid progenitors. The CD7+phenotype distinguishes primitive human lymphoid progenitors from pluripotent stem cells, thus allowing the study of regulation of early human lymphopoiesis and providing an alternative to pluripotent stem cells for genetic manipulation and transplantation.
45
Arinobu, Yojiro, Shin-ichi Mizuno, Yong Chong, Hirokazu Shigematsu, Tadafumi Iino, Hiromi Iwasaki, Thomas Graf, et al. "Reciprocal Activation of GATA-1 and PU.1 Marks Initial Specification of Hematopoietic Stem Cells into Myelo-Erythroid and Myelo-Lymphoid Lineages." Blood 110, no. 11 (November 16, 2007): 1228. http://dx.doi.org/10.1182/blood.v110.11.1228.1228.
Full textAbstract:
Abstract Understanding how multipotent cells commit to each of their terminal fate potentials is an important aspect of stem cell biology. In adult murine hematopoiesis, HSCs with long-term self-renewal potential reside within the Lin −Sca-1+c-Kit+ (LSK) fraction having CD34−, Thy1lo, and Flt3/Flk2−phenotypes. The LSK cells having CD34+, Thy1−, and/or Flt3+ phenotypes are capable of multi-lineage reconstitution only for a short-term, and therefore should contain multipotent progenitors (MPPs). In terms of developmental steps downstream of MPPs, there has been a controversy. The existence of prospectively isolatable progenitors capable of generating only myeloerythroid cells (common myeloid progenitor: CMP) or only lymphocytes (common lymphoid progenitors: CLP) outside the LSK fraction suggests that the first commitment step after the MPP stage is the strict bifurcation of lymphoid vs. myeloid pathway. Recently, however, several studies have suggested that the lineage commitment could occur within the LSK fraction, preceding the proposed bifurcation of myeloid and lymphoid pathways. For example, MPPs expressing Flt3 at a high level retained granulocytes/monocytes (GM) but not megakaryocyte/erythrocyte (MegE) potential together with lymphoid potential, suggesting the existence of common progenitor for GM and lymphoid lineages within the LSK fraction. Based on this data, the coupled loss of self-renewal activity and MegE potential in the early HSC commitment has been proposed. How can we reconcile the controversy in the early hematopoietic lineage map? By utilizing mice having GATA-1 or PU.1 transcriptional reporters, we here present a high-resolution map containing new lineage-restricted progenitor populations within the MPP population of CD34+ LSK phenotype. Initial upregulation of GATA-1 and PU.1 occurred independently at the MPP stage. The GATA-1+ MPP displayed potent myeloerythroid potential without giving rise to lymphocytes, whereas the PU.1+ MPP showed granulocyte/monocyte/lymphoid-restricted progenitor activity without megakaryocyte/erythroid differentiation. Furthermore, GATA-1+ and PU.1+ MPPs possessed huge expansion potential, and differentiated into the original CMPs and CLPs, respectively. Thus, the reciprocal activation of GATA-1 and PU.1 primarily organizes hematopoietic lineage fate decision to form the earliest hematopoietic branchpoint that comprises new, isolatable myeloerythroid and myelolymphoid progenitor populations.
46
Dakic, Aleksandar, Donald Metcalf, Ladina Di Rago, Sandra Mifsud, Li Wu, and Stephen L. Nutt. "PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis." Journal of Experimental Medicine 201, no. 9 (May 2, 2005): 1487–502. http://dx.doi.org/10.1084/jem.20050075.
Full textAbstract:
Although the transcription factor PU.1 is essential for fetal lymphomyelopoiesis, we unexpectedly found that elimination of the gene in adult mice allowed disturbed hematopoiesis, dominated by granulocyte production. Impaired production of lymphocytes was evident in PU.1-deficient bone marrow (BM), but myelocytes and clonogenic granulocytic progenitors that are responsive to granulocyte colony-stimulating factor or interleukin-3 increased dramatically. No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry; however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation. PU.1 deletion in granulocyte-macrophage progenitors, but not in common myeloid progenitors, resulted in excess granulocyte production; this suggested specific roles of PU.1 at different stages of myeloid development. These findings emphasize the distinct nature of adult hematopoiesis and reveal that PU.1 regulates the specification of the multipotent lymphoid and myeloid compartments and restrains, rather than promotes, granulopoiesis.
47
Punzel, M., S. D. Wissink, J. S. Miller, K. A. Moore, I. R. Lemischka, and C. M. Verfaillie. "The Myeloid-Lymphoid Initiating Cell (ML-IC) Assay Assesses the Fate of Multipotent Human Progenitors In Vitro." Blood 93, no. 11 (June 1, 1999): 3750–56. http://dx.doi.org/10.1182/blood.v93.11.3750.411a37_3750_3756.
Full textAbstract:
Hematopoietic stem cells (HSC) are cells with self-renewing multilineage differentiation potential. Although engraftment in xenogeneic recipients can be used to measure human HSC, these assays do not allow assessment of individual progenitors. We developed an in vitro assay that allows the identification of a single human bone marrow progenitor closely related to HSC, which we termed “Myeloid-Lymphoid Initiating Cell,” or ML-IC, because it is capable of generating multiple secondary progenitors that can reinitiate long-term myeloid and lymphoid hematopoiesis in vitro. The assay is done in contact with murine AFT024 fetal liver stromal cells and with Flt3-Ligand, stem cell factor, and interleukin-7. In this assay, 0.2% to 1.7% of Lin−/34+/DRdim cells could generate 1 to 3 long-term culture initiating cells (LTC-IC) as well as 1 to 4 NK-IC after 4 to 6 weeks. In addition, this assay measures contribution of net-progenitor conservation and net-progenitor proliferation over time, providing insight in the fate of individual LTC-IC and NK-IC. This assay will prove useful to enumerate the number of very primitive human progenitors with multilineage differentiation potential, as well as to evaluate future ex vivo culture conditions.
48
Saran, Namita, Marcin Łyszkiewicz, Jens Pommerencke, Katrin Witzlau, Ramin Vakilzadeh, Matthias Ballmaier, Harald von Boehmer, and Andreas Krueger. "Multiple extrathymic precursors contribute to T-cell development with different kinetics." Blood 115, no. 6 (February 11, 2010): 1137–44. http://dx.doi.org/10.1182/blood-2009-07-230821.
Full textAbstract:
Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.
49
Huntly, Brian J. P., Sarah Jayne Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, et al. "Early Loss of CREBBP Confers Malignant Stem Cell Properties on Lymphoid Progenitors." Blood 128, no. 22 (December 2, 2016): 460. http://dx.doi.org/10.1182/blood.v128.22.460.460.
Full textAbstract:
Abstract Loss-of-function mutations of the cyclic-AMP response element binding protein, binding protein (CREBBP) gene have recently been described at high frequencies across a spectrum of lymphoid malignancies, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The multiple effects of this epigenetic regulator on developmental and homeostatic processes have been extensively studied, however, exactly how CREBBP functions as a tumor suppressor and the reasons for its particular predilection for suppression of lymphoid tumors remains unclear. In addition, for many mature lymphoid malignancies, the existence of cancer stem cells is unproven and their provenance and the initial target cell for transformation a source of ongoing debate. Here we use multiple mouse strains to model loss of Crebbp in different lymphoid compartments to address these questions. We demonstrate that early loss of Crebbp in hematopoietic stem and progenitor cells (HSPC), through disruption by the Mx1-Cre recombinase, leads to increased development of hematological malignancies, particularly of the B-lymphoid lineage that mimic features of human lymphomas. Theses B-cell malignancies are of long latency and are preceded by significant alterations in the proliferation, self-renewal and differentiation of lymphoid progenitors, allowing hyperproliferative lymphoid progenitors whose differentiation is blocked to accumulate. Using an aberrant surface phenotype that resembles the eventual tumor, we identify a pre-malignant population in the peripheral blood of animals that is often evident many months before any disease characteristics. We demonstrate pre-malignant stem cell characteristics for this population in functional experiments, where it generates high level reconstitution of peripheral blood in transplant recipients, but only gives rise to disease in these animals after a long latency. We also utilize this unique cellular population in longitudinal genome scale analyses (clonality, RNA-Seq, ChIP-Seq and exome sequencing) to document the mechanisms of malignant evolution. Linking the increased rate of mutation we describe to Crebbp loss, we also demonstrate increased DNA damage and an altered DNA-damage response in premalignant lymphoid progenitors. Importantly, using a Cd19-Cre recombinase that excises only within committed lymphoid cells, we are able to demonstrate that when Crebbp is lost at a later stage of lymphoid development, the marked cellular abnormalities described above are completely lost and the development of tumors is no different from normal (Figure, below). Taken together, these findings define the developmental stage-specific tumor suppressor functions of Crebbp and shed light on the cellular origins and subsequent evolution of lymphoid malignancies. In addition, the altered response to DNA damage that we demonstrate upon loss of Crebbp, allied to the increased exposure to physiological DNA-damage during lymphoid ontogeny offers an explanation for the high incidence of CREBBP mutations in mature lymphoid malignancies. Figure Left panel, Kaplan Meier graph for Mx1-Cre Crebbp mice with loss of Crebbp in the HSPC compartment demonstrates significantly shorter survival vs WT littermates with intact expression of Crebbp. In contrast, when Crebbp is excised in a later lymphoid compartment through Cd19-Cre mediated recombination, right panel, no difference in survival is noted from WT littermate controls. Figure. Left panel, Kaplan Meier graph for Mx1-Cre Crebbp mice with loss of Crebbp in the HSPC compartment demonstrates significantly shorter survival vs WT littermates with intact expression of Crebbp. In contrast, when Crebbp is excised in a later lymphoid compartment through Cd19-Cre mediated recombination, right panel, no difference in survival is noted from WT littermate controls. Disclosures Huntly: Novartis: Speakers Bureau; BMS: Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau.
50
Miller, Jeffrey S., Felipe Prosper, and Valarie McCullar. "Natural Killer (NK) Cells Are Functionally Abnormal and NK Cell Progenitors Are Diminished in Granulocyte Colony-Stimulating Factor–Mobilized Peripheral Blood Progenitor Cell Collections." Blood 90, no. 8 (October 15, 1997): 3098–105. http://dx.doi.org/10.1182/blood.v90.8.3098.
Full textAbstract:
Abstract Granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood progenitor cell (PBPC) collections are increasingly emerging as the graft of choice in many centers for autologous transplantation, and with increasing frequency for allogeneic transplantation. However, the role of myeloid cytokines in lymphoid function, lymphoid progenitors, and immune-mediated antitumor responses is not known. We studied PBPC collections from normal donors mobilized with G-CSF (10 μg/kg). CD56+/CD3− natural killer (NK) cells sorted from PBPC products exhibited a diminished ability to kill tumor targets, were less responsive in acquiring increased cytolysis with interleukin-2 (IL-2), and proliferated less than NK cells from normal unprimed peripheral blood. This abnormality was not explained by a change in phenotype of NK cells normally circulating in the blood after G-CSF administration. We could not demonstrate any direct suppressive effect on normal unprimed NK cell proliferation or cytotoxicity by culture with pharmacologic concentrations of G-CSF. We next evaluated the effects of G-CSF on CD34+ NK cell progenitors. CD34+/CD2+, CD34+/CD7+, and CD34+/CD10+ progenitors were markedly diminished in G-CSF–mobilized PBPC products. CD34+ cells cultured in limiting dilution assays showed a sixfold decrease in NK cell progenitors when derived from G-CSF–mobilized CD34+ PBPCs compared with CD34+ cells derived from unprimed marrow. The finding of decreased NK cell function, inhibited proliferation, and diminished cloning frequency after treatment with G-CSF could be mimicked in vitro by culture of primitive marrow progenitors (CD34+, lineage-negative, HLA-DR−) on stromal layers in the presence of exogenous G-CSF. The findings presented here show that G-CSF administration to normal donors decreases NK cell function and the relative frequency of NK cell progenitors within the CD34+ progenitor population. Overcoming this diminished lymphoid capacity may be important to facilitate early posttransplant immunotherapy. Our in vitro model will be used in future studies to determine the mechanism of the G-CSF–induced suppression of NK cell progenitors, which may occur early in the differentiation process.