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Sood, Raman, Milton English, Christiane Belele, Rebecca Haskins, Anthony Burnetti, Jagman Chahal i Pu Paul Liu. "Identification of Three Phases of Hematopoieisis in Zebrafish and Their Differential Requirements for Runx1 and Gata1 Functions." Blood 110, nr 11 (16.11.2007): 202. http://dx.doi.org/10.1182/blood.v110.11.202.202.
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Abstract Primitive hematopoiesis in the zebrafish takes place in the intermediate cell mass (ICM), while definitive hematopoiesis takes place in the kidney. Recently, a new transition site called caudal hematopoietic tissue (CHT), or posterior blood island (PBI) was identified. Using lineage tracing the hematopoietic cells originating from ICM were shown to transit through CHT and eventually populate kidney and thymus. However, the lineage relationship of the cells at these sites and the genetic control of early hematopoiesis in the zebrafish remain to be resolved. Transcription factors Gata1 and Runx1 are required for primitive and definitive hematopoiesis respectively in mammals, and are likely candidates as key hematopoietic regulators in the zebrafish. By ENU mutagenesis and reverse genetic screening, we have generated a zebrafish runx1 mutant line with a truncation mutation, W84X, in the runt homology domain and a hypomorphic gata1 mutant line with a missense mutation, T301K, in the C-terminal zinc finger domain. We used hypomorphic allele in combination with the previously characterized gata1 null mutation, vlad tepes (vlt) to assess the requirements for gata1 during primitive and definitive hematopoiesis. Gel-shift analysis showed that the T301K gata1 protein had reduced binding affinity for DNA as opposed to complete lack of binding by the vlt mutant protein. This reduced activity is sufficient for hematopoieisis since gata1T301K/T301K embryos had normal circulation at all stages and survived to adulthood, while gata1vlt/vlt embryos never developed circulation and died around 11–15 days post fertilization (dpf). On the other hand, compound heterozygous gata1T301K/vlt embryos lacked circulation until 7 dpf, regained circulation around 8–11dpf and survived to adulthood. Analysis of markers for definitive hematopoiesis by in situ hybridzationan and crossing with transgenic Tg(cd41-GFP) fish indicated that definitive hematopoiesis was normal. These data suggest dosage effect of gata1 function during primitive and definitive stages of hematopoiesis, indicating that partial gata1 activity was sufficient for definitive hematopoiesis. Furthermore, we identified two phases of definitive hematopoiesis by characterization of the runx1 truncation mutation. runx1W84X/W84X embryos had normal circulation until 7dpf, gradually lost circulation around 8–11dpf, stayed bloodless until 20–25dpf and the surviving embryos regained circulation, while majority of them died during the bloodless phase. Approximately twenty percent of runx1W84X/W84X embryos survived to adulthood. By in situ hybridization, definitive hematopoietic stem cell markers, runx1 and c-myb, were not detectable in the runx1 mutant embryos. However, crossing with transgenic Tg(cd41-GFP) fish showed that cd41+ stem cells of definitive hematopoiesis were retained in the runx1W84X/W84X embryos and migrated from ICM to CHT and then to kidney as wildtype clutch-mates. In runx1W84X/W84X mutant Tg(gata1-GFP) and Tg(cd41-GFP) embryos the bloodless phase was accompanied by lack of gata1-GFP+ erythroid cells and cd41-GFP+ circulating thrombocytes, which reappeared after recovery of circulation. These data suggest that there are two phases of definitive hematopoiesis: larval and adult, and that runx1 is absolutely required for the larval stage. In conclusion, we have identified three stages of hematopoiesis in the zebrafish and revealed the differential dosage requirement for gata1 and runx1 during these three stages.
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Wu, Jiang, Weiwei Zhang, Qian Ran, Yang Xiang, Jiang F. Zhong, Shengwen Calvin Li i Zhongjun Li. "The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis". Stem Cells International 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/1540148.
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Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation.
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Gerosa, Rahel C., Steffen Boettcher, Larisa V. Kovtonyuk, Annika Hausmann, Wolf-Dietrich Hardt, Juan Hidalgo, César Nombela-Arrieta i Markus G. Manz. "CXCL12-abundant reticular cells are the major source of IL-6 upon LPS stimulation and thereby regulate hematopoiesis". Blood Advances 5, nr 23 (2.12.2021): 5002–15. http://dx.doi.org/10.1182/bloodadvances.2021005531.
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Abstract Hematopoiesis is maintained by hematopoietic stem and progenitor cells that are located in the bone marrow (BM) where they are embedded within a complex supportive microenvironment consisting of a multitude of various non-hematopoietic and hematopoietic cell types. The BM microenvironment not only regulates steady-state hematopoiesis by provision of growth factors, cytokines, and cell–cell contact but is also an emerging key player during the adaptation to infectious and inflammatory insults (emergency hematopoiesis). Through a combination of gene expression analyses in prospectively isolated non-hematopoietic BM cell populations and various mouse models, we found that BM CXCL12-abundant reticular (CAR) cells are a major source of systemic and local BM interleukin-6 (IL-6) levels during emergency hematopoiesis after lipopolysaccharide (LPS) stimulation. Importantly, although IL-6 is dispensable during the initial phase of LPS-induced emergency hematopoiesis, it is required to sustain an adequate hematopoietic output during chronic repetitive inflammation. Our data highlight the essential role of the non-hematopoietic BM microenvironment for the sensing and integration of pathogen-derived signals into sustained demand-adapted hematopoietic responses.
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Smith, Clayton. "Hematopoietic Stem Cells and Hematopoiesis". Cancer Control 10, nr 1 (styczeń 2003): 9–16. http://dx.doi.org/10.1177/107327480301000103.
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Background The highly orchestrated process of blood cell development and homeostasis is termed “hematopoiesis.” Understanding the biology of hematopoietic stem cells as well as hematopoiesis is important to developing improved treatments for hematologic malignancies, congenital disorders, chemotherapy-related cytopenias, and blood and marrow transplants. Methods The author reviews the current state of the art regarding hematopoietic stem cells and hematopoiesis. Results Several new concepts, including stem cell plasticity, suggest the possibility that stem cells may have the ability to differentiate into other tissues in addition to blood cells. Conclusions While much is known about hematopoietic stem cells and hematopoiesis, much remains to be clarified about the environmental and genetic processes that govern the growth and development of the blood system. In addition, careful studies remain to be conducted to determine whether hematopoietic stem cells can differentiate into extra-hematopoietic tissues.
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Wei, Chuijin, Pei Yu i Lin Cheng. "Hematopoietic Reprogramming Entangles with Hematopoiesis". Trends in Cell Biology 30, nr 10 (październik 2020): 752–63. http://dx.doi.org/10.1016/j.tcb.2020.07.006.
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Zon, LI. "Developmental biology of hematopoiesis". Blood 86, nr 8 (15.10.1995): 2876–91. http://dx.doi.org/10.1182/blood.v86.8.2876.bloodjournal8682876.
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The cellular and environmental regulation of hematopoiesis has been generally conserved throughout vertebrate evolution, although subtle species differences exist. The factors that regulate hematopoietic stem cell homeostasis may closely resemble the inducers of embryonic patterning, rather than the factors that stimulate hematopoietic cell proliferation and differentiation. Comparative study of embryonic hematopoiesis in lower vertebrates can generate testable hypotheses that similar mechanisms occur during hematopoiesis in higher species.
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Ozbudak, Irem H., Konstantin Shilo, Sabine Hale, Nadine S. Aguilera, Jeffrey R. Galvin i Teri J. Franks. "Alveolar Airspace and Pulmonary Artery Involvement by Extramedullary Hematopoiesis: A Unique Manifestation of Myelofibrosis". Archives of Pathology & Laboratory Medicine 132, nr 1 (1.01.2008): 99–103. http://dx.doi.org/10.5858/2008-132-99-aaapai.
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Abstract Pulmonary extramedullary hematopoiesis is a rare manifestation of myelofibrosis. We encountered a unique case of pulmonary extramedullary hematopoiesis occurring in a 59-year-old white man, where in addition to the typical foci of interstitial hematopoietic cells, a surgical lung biopsy showed airspace and arterial wall involvement. Airspace foci were associated with acute and organizing alveolar hemorrhage, while within arteries the hematopoietic elements had a striking predilection for the vascular intima. The hematopoietic foci included erythroid precursors, myeloid precursors, and megakaryocytes, which were immunoreactive with hemoglobin, myeloperoxidase, and CD61, respectively. Whether extramedullary hematopoiesis represents in situ embryonic stem cell differentiation or a compensatory seeding of hematopoietic cells from the bone marrow remains to be elucidated. However, familiarity with these findings in the lung could be helpful in uncovering occult hematological disorders accompanied by extramedullary hematopoiesis. Extramedullary hematopoiesis should also be considered as a cause of pulmonary hemorrhage, especially in the setting of myelofibrosis.
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Zon, LI. "Developmental biology of hematopoiesis". Blood 86, nr 8 (15.10.1995): 2876–91. http://dx.doi.org/10.1182/blood.v86.8.2876.2876.
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Abstract The cellular and environmental regulation of hematopoiesis has been generally conserved throughout vertebrate evolution, although subtle species differences exist. The factors that regulate hematopoietic stem cell homeostasis may closely resemble the inducers of embryonic patterning, rather than the factors that stimulate hematopoietic cell proliferation and differentiation. Comparative study of embryonic hematopoiesis in lower vertebrates can generate testable hypotheses that similar mechanisms occur during hematopoiesis in higher species.
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Testa, Ugo, Germana Castelli i Elvira Pelosi. "CLONAL HEMATOPOIESIS: ROLE IN HEMATOLOGIC NON-HEMATOLOGIC". Mediterranean Journal of Hematology and Infectious Diseases 14, nr 1 (27.08.2022): e2022069. http://dx.doi.org/10.4084/mjhid.2022.069.
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Hematopoietic stem cells (HSCs) ensure the coordinated and balanced production of all hematopoietic cell types throughout life. Aging is associated with a gradual decline of the self-renewal and regenerative potential of HSCs and with the development of clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is a term defining the clonal expansion of genetically variant hematopoietic cells bearing one or more gene mutations and/or structural variants (such as copy number alterations). CHIP increases exponentially with age and is associated with cancers, including hematologic neoplasia, cardiovascular and other diseases. The presence of CHIP consistently increases the risk of hematologic malignancy, particularly in individuals who have CHIP in association with peripheral blood cytopenia.
Key words: hematopoiesis, hematopoietic stem cells, clonal hematopoiesis, gene mutations, next generation sequencing.
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Papa, Veronica, Luisa Marracino, Francesca Fortini, Paola Rizzo, Gianluca Campo, Mauro Vaccarezza i Francesco Vieceli Dalla Sega. "Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review". Journal of Clinical Medicine 9, nr 8 (2.08.2020): 2480. http://dx.doi.org/10.3390/jcm9082480.
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Some random mutations can confer a selective advantage to a hematopoietic stem cell. As a result, mutated hematopoietic stem cells can give rise to a significant proportion of mutated clones of blood cells. This event is known as “clonal hematopoiesis.” Clonal hematopoiesis is closely associated with age, and carriers show an increased risk of developing blood cancers. Clonal hematopoiesis of indeterminate potential is defined by the presence of clones carrying a mutation associated with a blood neoplasm without obvious hematological malignancies. Unexpectedly, in recent years, it has emerged that clonal hematopoiesis of indeterminate potential carriers also have an increased risk of developing cardiovascular disease. Mechanisms linking clonal hematopoiesis of indeterminate potential to cardiovascular disease are only partially known. Findings in animal models indicate that clonal hematopoiesis of indeterminate potential-related mutations amplify inflammatory responses. Consistently, clinical studies have revealed that clonal hematopoiesis of indeterminate potential carriers display increased levels of inflammatory markers. In this review, we describe progress in our understanding of clonal hematopoiesis in the context of cancer, and we discuss the most recent findings linking clonal hematopoiesis of indeterminate potential and cardiovascular diseases.
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Fuchs, Anja G., Darlene Monlish, Sarbani Ghosh, Shin-Wen Chang, Grant V. Bochicchio, Laura G. Schuettpelz i Isaiah R. Turnbull. "Trauma Induces Emergency Hematopoiesis through IL-1/MyD88-Dependent Production of G-CSF". Journal of Immunology 202, nr 1_Supplement (1.05.2019): 118.3. http://dx.doi.org/10.4049/jimmunol.202.supp.118.3.
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Abstract The acute inflammatory response to infection or injury dramatically increases the hematopoietic demand on the bone marrow to replace effector leukocytes consumed in the inflammatory response. In the setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating hematopoietic stem and progenitor cells to proliferate, thereby providing progeny for accelerated myelopoiesis. Sterile tissue injury due to trauma also increases leukocyte demand; however, the effect of sterile tissue injury on hematopoiesis is not well described. We used a mouse model of multisystem injury to investigate the effects of these injuries on bone marrow progenitor frequencies and phenotypes. We find that tissue injury alone induces emergency hematopoiesis in mice subjected to polytrauma. This process is driven by IL-1/MyD88-dependent production of G-CSF. G-CSF induces expansion of hematopoietic progenitors including hematopoietic stem cells and multipotent progenitors and increases the frequency of myeloid-skewed progenitors. These data provide the first comprehensive description of injury-induced emergency hematopoiesis and identify an IL-1/MyD88/G-CSF dependent pathway as the key regulator of emergency hematopoiesis after injury.
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Matula, Zsolt, Gyöngyi Kudlik, Veronika Urbán S. i Ferenc Uher. "Quo vadis, hematológia?" Orvosi Hetilap 157, nr 46 (listopad 2016): 1819–29. http://dx.doi.org/10.1556/650.2016.30580.
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For decades, developing hematopoietic cells have been strictly compartmentalized into a small population of multipotent self-renewing hematopoietic stem cells, multipotent hematopoietic progenitor cells that are undergoing commitment to myeloid or lymphoid fates, and unipotent precursor cells that mature towards peripheral blood and immune cells. Recent studies, however, have provided a battery of findings that cannot be explained by this “classical” hierarchical model for the architecture of hematopoiesis. It is emerging that heterogeneous hematopoietic stem cell populations in the bone marrow coexist, each with distinct, preprogrammed differentiation and proliferation behaviors. Three subsets can be distinguished among them: myeloid-biased (α), balanced (β), and lymphoid-biased (γ/δ) hematopoietic stem cells. The ratio of these hematopoietic stem cell subsets is developmentally regulated in the foetal liver and hematopoietic stem cells adult bone marrow, and coordinately gives rise to hematopoiesis. Beta- and γ/δ-hematopoietic stem cells are found predominantly early in the life of an organism, whereas α-hematopoietic stem cells accumulate in aged mice and humans. In addition, new sophisticated genetic experiments in mice have identified a major role of long-lived, committed progenitor cells downstream from hematopoietic stem cells as drivers of normal adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs qualitatively and quantitatively from normal steady-state hematopoiesis. These findings have important implications for understanding in situ the regulation of haematopoiesis in health and disease. Orv. Hetil., 2016, 157(46), 1819–1829.
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Sood, Raman, i Paul Liu. "Novel Insights into the Genetic Controls of Primitive and Definitive Hematopoiesis from Zebrafish Models". Advances in Hematology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/830703.
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Hematopoiesis is a dynamic process where initiation and maintenance of hematopoietic stem cells, as well as their differentiation into erythroid, myeloid and lymphoid lineages, are tightly regulated by a network of transcription factors. Understanding the genetic controls of hematopoiesis is crucial as perturbations in hematopoiesis lead to diseases such as anemia, thrombocytopenia, or cancers, including leukemias and lymphomas. Animal models, particularly conventional and conditional knockout mice, have played major roles in our understanding of the genetic controls of hematopoiesis. However, knockout mice for most of the hematopoietic transcription factors are embryonic lethal, thus precluding the analysis of their roles during the transition from embryonic to adult hematopoiesis. Zebrafish are an ideal model organism to determine the function of a gene during embryonic-to-adult transition of hematopoiesis since bloodless zebrafish embryos can develop normally into early larval stage by obtaining oxygen through diffusion. In this review, we discuss the current status of the ontogeny and regulation of hematopoiesis in zebrafish. By providing specific examples of zebrafish morphants and mutants, we have highlighted the contributions of the zebrafish model to our overall understanding of the roles of transcription factors in regulation of primitive and definitive hematopoiesis.
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Ishigaki, Taro, Kazuhiro Sudo, Takashi Hiroyama, Kenichi Miharada, Haruhiko Ninomiya, Shigeru Chiba, Toshiro Nagasawa i Yukio Nakamura. "Human Hematopoietic Stem Cells Can Survive In Vitro for Several Months". Advances in Hematology 2009 (2009): 1–7. http://dx.doi.org/10.1155/2009/936761.
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We previously reported that long-lasting in vitro hematopoiesis could be achieved using the cells differentiated from primate embryonic stem (ES) cells. Thus, we speculated that hematopoietic stem cells differentiated from ES cells could sustain long-lasting in vitro hematopoiesis. To test this hypothesis, we investigated whether human hematopoietic stem cells could similarly sustain long-lasting in vitro hematopoiesis in the same culture system. Although the results varied between experiments, presumably due to differences in the quality of each hematopoietic stem cell sample, long-lasting in vitro hematopoiesis was observed to last up to nine months. Furthermore, an in vivo analysis in which cultured cells were transplanted into immunodeficient mice indicated that even after several months of culture, hematopoietic stem cells were still present in the cultured cells. To the best of our knowledge, this is the first report to show that human hematopoietic stem cells can survive in vitro for several months.
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Haney, Michael, Archana Shankar, Leonid Olender, Ian Hsu, Masashi Miyauchi, Grace Meaker, Satoshi Kaito i in. "Identification of the Saga Complex As a Key Regulator of Hematopoiesis". Blood 144, Supplement 1 (5.11.2024): 5623. https://doi.org/10.1182/blood-2024-205547.
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The hematopoietic system declines with age, and its dysfunction is associated with many diseases, ranging from infections to cancers. However, the processes that sustain lifelong hematopoiesis remain incompletely understood. To identify genetic regulators of hematopoiesis, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform. Targeting ~2000 genes with this platform, we identified SAGA complex members Tada2b and Taf5l as key regulators of hematopoiesis. Genetic perturbation of Tada2b or Taf5l in murine HSCs led to significant HSC expansion ex vivo, strongly inhibited hematopoiesis in vivo, led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. These results were validated in an ex vivo human HSC culture as well, and loss of these SAGA complex components enhanced the cell outgrowth and drives interferon pathway gene expression in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression in humans. Altogether, this study offers a new platform to screen genetic regulators of hematopoiesis and identifies novel regulators of hematopoiesis.
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Arnold, Olivia, Theresa Bluemn, Cary Stelloh, Sridhar Rao i Nan Zhu. "The SWI/SNF subunit ARID1B is important for regenerative ability of hematopoietic stem cells in normal hematopoiesis". PLOS ONE 19, nr 10 (24.10.2024): e0312616. http://dx.doi.org/10.1371/journal.pone.0312616.
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The Switch/Sugar non-fermenting (SWI/SNF) nucleosome remodeling complexes are essential for normal hematopoiesis. The Brg1/Brm associated factor (BAF) is a form of mammalian SWI/SNF that is distinguished by the presence of either ARID1A or ARID1B protein. In this study, we used hematopoietic specific Cre mouse models to assess the function of Arid1b in blood development. We found Arid1b loss did not affect steady state hematopoiesis or hematopoietic regeneration. Nonetheless, Arid1b null hematopoietic stem and progenitor cells have reduced ability to reconstitute hematopoietic system compared to wild type cells. Overall, our data indicate Arid1b is largely dispensable for normal hematopoiesis but impairs the regenerative ability of HSPCs.
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Belyavsky, Alexander, Nataliya Petinati i Nina Drize. "Hematopoiesis during Ontogenesis, Adult Life, and Aging". International Journal of Molecular Sciences 22, nr 17 (26.08.2021): 9231. http://dx.doi.org/10.3390/ijms22179231.
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In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.
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Sleptsov, A. A., M. S. Nazarenko i V. Р. Puzyrev. "Common in atherogenesis and carcinogenesis: clonal hematopoiesis". Russian Journal of Cardiology 28, nr 10 (17.07.2023): 5511. http://dx.doi.org/10.15829/1560-4071-2023-5511.
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Clonal hematopoiesis is a common age-dependent state accompanied by the expansion of mutant hematopoietic stem cells as a result of somatic mutations and is associated with a high risk of hematopoietic neoplasms and cardiovascular diseases. Clonal hematopoiesis in human ontogenesis occurs asymptomatically, and the fraction of mutant clones can exceed more than 2% of the total pool of circulating nucleated blood cells by age 70. Due to the variability of the accumulation rate of mutant clones, signs of clonal hematopoiesis can be observed at a younger age. Clonal hematopoiesis may act as a benign, precancerous condition and a strong factor for acute cardiovascular events such as myocardial infarction and stroke. Current evidence indicates that somatic mutations in driver genes of clonal hematopoiesis significantly increase the risk of acute conditions such as acute myeloid leukemia and acute myocardial infarction. The high mortality and morbidity of cardiovascular and cancer diseases, and their strong association with clonal hematopoiesis, make it of indeterminate potential worthy of close attention.
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Drize, Nina, i Nataliya Petinati. "What do we know about the participation of hematopoietic stem cells in hematopoiesis?" F1000Research 4 (29.10.2015): 1177. http://dx.doi.org/10.12688/f1000research.6459.1.
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The demonstrated presence in adult tissues of cells with sustained tissue regenerative potential has given rise to the concept of tissue stem cells. Assays to detect and measure such cells indicate that they have enormous proliferative potential and usually an ability to produce all or many of the mature cell types that define the specialized functionality of the tissue. In the hematopoietic system, one or only a few cells can restore lifelong hematopoiesis of the whole organism. To what extent is the maintenance of hematopoietic stem cells required during normal hematopoiesis? How does the constant maintenance of hematopoiesis occur and what is the behavior of the hematopoietic stem cells in the normal organism? How many of the hematopoietic stem cells are created during the development of the organism? How many hematopoietic stem cells are generating more mature progeny at any given moment? What happens to the population of hematopoietic stem cells in aging? This review will attempt to describe the results of recent research which contradict some of the ideas established over the past 30 years about how hematopoiesis is regulated.
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Link, Daniel C. "Clonal Evolution During Stress Hematopoiesis". Blood 130, Suppl_1 (7.12.2017): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-38.sci-38.
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Hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations with age resulting in a heterogeneous cell population, with each HSPC possessing its own unique set of private mutations. HSPCs that acquire somatic mutations that confer a competitive fitness advantage relative to their normal counterparts may clonally expand. Indeed, several groups have documented the presence of clonal hematopoiesis in healthy individuals. Although originally thought to be limited to older individuals, a recent study using an ultra-sensitive sequencing technique showed that expanded hematopoietic clones are detectable in the majority of healthy 50-60-year-old individuals. With some notable exceptions, the same genes that are commonly mutated in clonal hematopoiesis also are somatically mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, only a small fraction of individuals with clonal hematopoiesis subsequently develop a myeloid malignancy and the size of the mutant clone in clonal hematopoiesis can remain stable for years without disease progression. These observations raise several questions that will be addressed in this presentation. What drives expansion of hematopoietic clones? What role do external hematopoietic stressors, such as exposure to chemotherapy, play in the development of clonal hematopoiesis? Why do so few people with clonal hematopoiesis develop a myeloid malignancy, and are there certain mutations that confer a higher risk of transformation? Disclosures No relevant conflicts of interest to declare.
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Yan, Hannah, Forrest C. Walker, Arushana Ali, Hyojeong Han, Lin Tan, Lucas Veillon, Philip L. Lorenzi, Megan T. Baldridge i Katherine Y. King. "The bacterial microbiota regulates normal hematopoiesis via metabolite-induced type 1 interferon signaling". Blood Advances 6, nr 6 (15.03.2022): 1754–65. http://dx.doi.org/10.1182/bloodadvances.2021006816.
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Abstract Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling. Using conditional knockout and chimeric mice, we found that the microbiota induced STAT1 signaling in non-myeloid hematopoietic cells to support hematopoiesis and that STAT1 signaling was specifically dependent on type I interferons (IFNs). Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells with antibiotic treatment. In addition, we discovered that oral administration of a commensal-derived product, NOD1 ligand, rescues the hematopoietic defects induced by antibiotics in mice. Using metabolomics, we identified additional microbially produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics, including phosphatidylcholine and γ-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promotes normal hematopoiesis and identify microbial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia.
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Priestley, Gregory V., Linda M. Scott, Tatiana Ulyanova i Thalia Papayannopoulou. "Lack of α4 integrin expression in stem cells restricts competitive function and self-renewal activity". Blood 107, nr 7 (1.04.2006): 2959–67. http://dx.doi.org/10.1182/blood-2005-07-2670.
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AbstractAlpha4 integrin or VLA4 (CD49d/CD29) is a multitask molecule with wide expression within and outside the hematopoietic system. Because targeted ablation of α4 integrin leads to embryonic lethality, to study its effects on adult hematopoiesis, we used animals with conditional excision of α4 integrin (α4Δ/Δ) in hematopoietic cells. In such animals, we previously documented weakened bone marrow retention of progenitor cells during homeostasis and impaired homing and short-term engraftment after transplantation. In the present study we show that long-term repopulating cells lacking α4 integrins display a competitive disadvantage in hematopoietic reconstitution compared to normal competitors. Although initial dominance of α4+ competitors is due to their better homing and proliferative expansion early after transplantation, a progressive decline in contribution of α4Δ/Δ hematopoiesis is compatible with neither normal homing nor normal function of α4Δ/Δ hematopoietic stem cells (HSCs) in post-homing hematopoiesis. In the absence of α4+ competitor cells, α4Δ/Δ HSCs can establish long-term hematopoiesis in primary recipients, however, some resurgence of host hematopoiesis is evident, and it becomes dominant in secondary transplants, so that no survivors with exclusively α4Δ/Δ cells are seen in tertiary transplants. Collectively, our data provide compelling evidence that under regenerative stress α4 integrin assumes a greater importance than for maintenance of steady-state hematopoiesis.
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Ganuza, Miguel, Trent Hall, David Finkelstein, Yong-Dong Wang, Ashley Chabot, Guolian Kang, Wenjian Bi, Gang Wu i Shannon McKinney-Freeman. "The global clonal complexity of the murine blood system declines throughout life and after serial transplantation". Blood 133, nr 18 (2.05.2019): 1927–42. http://dx.doi.org/10.1182/blood-2018-09-873059.
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Abstract Although many recent studies describe the emergence and prevalence of “clonal hematopoiesis of indeterminate potential” in aged human populations, a systematic analysis of the numbers of clones supporting steady-state hematopoiesis throughout mammalian life is lacking. Previous efforts relied on transplantation of “barcoded” hematopoietic stem cells (HSCs) to track the contribution of HSC clones to reconstituted blood. However, ex vivo manipulation and transplantation alter HSC function and thus may not reflect the biology of steady-state hematopoiesis. Using a noninvasive in vivo color-labeling system, we report the first comprehensive analysis of the changing global clonal complexity of steady-state hematopoiesis during the natural murine lifespan. We observed that the number of clones (ie, clonal complexity) supporting the major blood and bone marrow hematopoietic compartments decline with age by ∼30% and ∼60%, respectively. Aging dramatically reduced HSC in vivo–repopulating activity and lymphoid potential while increasing functional heterogeneity. Continuous challenge of the hematopoietic system by serial transplantation provoked the clonal collapse of both young and aged hematopoietic systems. Whole-exome sequencing of serially transplanted aged and young hematopoietic clones confirmed oligoclonal hematopoiesis and revealed mutations in at least 27 genes, including nonsense, missense, and deletion mutations in Bcl11b, Hist1h2ac, Npy2r, Notch3, Ptprr, and Top2b.
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Growney, Joseph D., Hirokazu Shigematsu, Zhe Li, Benjamin H. Lee, Jennifer Adelsperger, Rebecca Rowan, David P. Curley i in. "Loss of Runx1 Perturbs Adult Hematopoiesis and Is Associated with a Myeloproliferative Phenotype." Blood 104, nr 11 (16.11.2004): 227. http://dx.doi.org/10.1182/blood.v104.11.227.227.
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Abstract Homozygous loss of function of Runx1 during murine development results in an embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis. In light of recent reports of disparate requirements for hematopoietic transcription factors during development as opposed to adult hematopoiesis, we employed a conditional gene targeting strategy to effect loss of Runx1 function in adult mice. In contrast with the critical role of Runx1 during development, Runx1 was not essential for hematopoiesis in the adult hematopoietic compartment, although there were a number of significant hematopoietic abnormalities observed. Runx1 excision had significant lineage specific effects on B- and T-cell maturation, as well as pronounced inhibition of common lymphocyte progenitor production. Runx1 excision also resulted in inefficient platelet production. Of note, Runx1 deficient mice developed a mild myeloproliferative phenotype characterized by an increase in peripheral blood neutrophils, an increase in myeloid progenitor populations, and extramedullary hematopoiesis comprised of maturing myeloid and erythroid elements. These findings indicate that Runx1 deficiency has markedly different consequences during development compared with adult hematopoiesis, and provides insights into the phenotypic manifestations of Runx1 deficiency in hematopoietic malignancies.
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Growney, Joseph D., Hirokazu Shigematsu, Zhe Li, Benjamin H. Lee, Jennifer Adelsperger, Rebecca Rowan, David P. Curley i in. "Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype". Blood 106, nr 2 (15.07.2005): 494–504. http://dx.doi.org/10.1182/blood-2004-08-3280.
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Abstract Homozygous loss of function of Runx1 (Runt-related transcription factor 1 gene) during murine development results in an embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis. In light of recent reports of disparate requirements for hematopoietic transcription factors during development as opposed to adult hematopoiesis, we used a conditional gene-targeting strategy to effect the loss of Runx1 function in adult mice. In contrast with the critical role of Runx1 during development, Runx1 was not essential for hematopoiesis in the adult hematopoietic compartment, though a number of significant hematopoietic abnormalities were observed. Runx1 excision had lineage-specific effects on B- and T-cell maturation and pronounced inhibition of common lymphocyte progenitor production. Runx1 excision also resulted in inefficient platelet production. Of note, Runx1-deficient mice developed a mild myeloproliferative phenotype characterized by an increase in peripheral blood neutrophils, an increase in myeloid progenitor populations, and extramedullary hematopoiesis composed of maturing myeloid and erythroid elements. These findings indicate that Runx1 deficiency has markedly different consequences during development compared with adult hematopoiesis, and they provide insight into the phenotypic manifestations of Runx1 deficiency in hematopoietic malignancies.
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Watt, Suzanne M., i Maria G. Roubelakis. "Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges". International Journal of Molecular Sciences 26, nr 2 (14.01.2025): 671. https://doi.org/10.3390/ijms26020671.
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Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent cells with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011–1012) of new cells generated daily in a healthy young human adult are of hematopoietic origin. Therapeutically, human HSCs have contributed to over 1.5 million hematopoietic cell transplants (HCTs) globally, making this the most successful regenerative therapy to date. We will commence this review by briefly highlighting selected key achievements (from 1868 to the end of the 20th century) that have contributed to this accomplishment. Much of our knowledge of hematopoiesis is based on small animal models that, despite their enormous importance, do not always recapitulate human hematopoiesis. Given this, we will critically review the progress and challenges faced in identifying adult human HSCs and tracing their lineage differentiation trajectories, referring to murine studies as needed. Moving forward and given that human hematopoiesis is dynamic and can readily adjust to a variety of stressors, we will then discuss recent research advances contributing to understanding (i) which HSPCs maintain daily steady state human hematopoiesis, (ii) where these are located, and (iii) which mechanisms come into play when homeostatic hematopoiesis switches to stress-induced or emergency hematopoiesis.
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Wan, Xiaoling, Lulu Liu, Peipei Zhou, Xinhui Hui, Qiaomei He, Fangfang Yu, Wei Zhang i in. "The nuclear receptor corepressor NCoR1 regulates hematopoiesis and leukemogenesis in vivo". Blood Advances 3, nr 4 (25.02.2019): 644–57. http://dx.doi.org/10.1182/bloodadvances.2018022756.
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Abstract Enhanced understanding of normal and malignant hematopoiesis pathways should facilitate the development of effective clinical treatment strategies for hematopoietic malignancies. Nuclear receptor corepressor 1 (NCoR1) has been implicated in transcriptional repression and embryonic organ development, but its role in hematopoiesis is yet to be fully elucidated. Here, we showed that hematopoietic-specific loss of NCoR1 leads to expansion of the hematopoietic stem cell (HSC) pool due to aberrant cell cycle entry of long-term HSCs under steady-state conditions. Moreover, NCoR1-deficient HSCs exhibited normal self-renewal capacity but severely impaired lymphoid-differentiation potential in competitive hematopoietic-reconstitution assays. Transcriptome analysis further revealed that several hematopoiesis-associated genes are regulated by NCoR1. In addition, NCoR1 deficiency in hematopoietic cells delayed the course of leukemia and promoted leukemia cell differentiation in an MLL-AF9–induced mouse model. NCoR1 and its partner, histone deacetylase 3, can modulate histone acetylation and gene transcription through binding the promoter regions of myeloid-differentiation genes. Our collective results support the critical involvement of NCoR1 in normal and malignant hematopoiesis in vivo.
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Shirin, A. D., R. Ya Vlasenko, N. Yu Anisimova, K. I. Kirgizov, T. T. Valiev, N. G. Stepanyan, T. Z. Aliev i in. "Hematopoietic stimulants in the treatment and prevention of graft-versus-host disease". Russian Journal of Pediatric Hematology and Oncology 9, nr 4 (2.02.2023): 64–74. http://dx.doi.org/10.21682/2311-1267-2022-9-4-64-74.
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Conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) are often accompanied by a period of aplasia characterized by severe neutropenia, anemia, and thrombocytopenia. Long-term antibacterial and immunosuppressive therapy in patients with graft-versus-host disease (GVHD) exacerbates hematopoietic depression. Colony-stimulating factors, erythropoietins, and thrombopoietin receptor agonists are used to correct hematological dysfunction in these patients. However, these drugs have side effects, and their stimulating effect, as a rule, is limited to one of the hematopoietic lineages. At the same time, in patients after HSCT, for the prevention and treatment of hematopoietic disorders against the background of GVHD, it is necessary to use drugs that promote the restoration of all hematopoietic cell lines. Inducers of Toll- and NOD-like receptors, stimulators of emergency hematopoiesis, can be considered as promising drugs for this category of patients. These compounds include bacterial derivatives and sulfated poly(oligo)saccharides capable of stimulating hematopoiesis, which allows us to consider them as promising stimulants of hematopoiesis for the treatment and prevention of disorders of the immune status and hematopoiesis in GVHD.
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Cousin, Béatrice, Louis Casteilla, Patrick Laharrague, Fabienne De Toni i Sandrine Poglio. "Adipose tissues, hematopoietic cells and hematopoiesis". Hématologie 17, nr 1 (styczeń 2011): 61–70. http://dx.doi.org/10.1684/hma.2011.0576.
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Shahidi, N. T. "Introduction: Hematopoiesis and Hematopoietic Growth Factors". Journal of Pediatric Hematology/Oncology 13, nr 4 (1991): 373–75. http://dx.doi.org/10.1097/00043426-199124000-00001.
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Grigorian, Melina, i Volker Hartenstein. "Hematopoiesis and hematopoietic organs in arthropods". Development Genes and Evolution 223, nr 1-2 (15.01.2013): 103–15. http://dx.doi.org/10.1007/s00427-012-0428-2.
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Yao, Longbiao, Takafumi Yokota, Lijun Xia, Paul W. Kincade i Rodger P. McEver. "Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells". Blood 106, nr 13 (15.12.2005): 4093–101. http://dx.doi.org/10.1182/blood-2005-02-0671.
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In vitro studies suggest that bone marrow endothelial cells contribute to multilineage hematopoiesis, but this function has not been studied in vivo. We used a Cre/loxP-mediated recombination to produce mice that lacked the cytokine receptor subunit gp130 in hematopoietic and endothelial cells. Although normal at birth, the mice developed bone marrow dysfunction that was accompanied by splenomegaly caused by extramedullary hematopoiesis. The hypocellular marrow contained myeloerythroid progenitors and functional repopulating stem cells. However, long-term bone marrow cultures produced few hematopoietic cells despite continued expression of gp130 in most stromal cells. Transplanting gp130-deficient bone marrow into irradiated wild-type mice conferred normal hematopoiesis, whereas transplanting wild-type bone marrow into irradiated gp130-deficient mice did not cure the hematopoietic defects. These data provide evidence that gp130 expression in the bone marrow microenvironment, most likely in endothelial cells, makes an important contribution to hematopoiesis.
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Lin, Hui-feng, Jing Zhang i Robert I. Handin. "Morpholino Knockdown of Jak2a Inhibits Primitive and Definitive Hematopoiesis in Zebrafish." Blood 108, nr 11 (16.11.2006): 636. http://dx.doi.org/10.1182/blood.v108.11.636.636.
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Abstract In zebrafish, the primitive wave of hematopoiesis is specified at 3 somites and is marked by two lateral stripes, which express early hematopoietic genes. The coalescence of these stripes forms the intermediate cell mass (ICM). This phase of hematopoiesis lasts about 4 days with erythrocytes entering the circulation 26 hpf. Between 36 and 42 hpf, the definitive wave of hematopoiesis commences. It is marked by the presence of hematopoietic progenitor cells in the dorsal aortic wall. Later in day 3 of development, hematopoietic stem cells from the dorsal aorta migrate into the interstitium of the mesonephros, which becomes the major hematopoietic organ in adult fish. Jak2 is a member of the Janus kinase family of non-receptor tyrosine kinases which plays an important role in hematopoiesis by transmitting cytokine-induced signals to associated STATs (signal transcription and activation transducers). The phosphorylated STATS migrate to the nucleus and induce gene transcription. The knockout of Jak2 in mice is embryonic lethal with a severe defect in erythropoiesis. We and others have observed that Jak2 is duplicated in zebrafish with one of the duplicated genes, jak2a, expressed exclusively in hematopoietic tissues. We have knocked down jak2a with anti-sense morpholinos to assess its role in hematopoiesis. O-dianisidine staining of embryos 2dpf shows a reduction in the primitive wave of erythropoiesis in the jak2a morphants. Using the CD41-GFP transgenic fish line we observed markedly reduced and, in some cases, the complete absence of circulating thrombocytes in jak2a morphants. To help understand how jak2a knockdown impairs hematopoiesis we examined the expression of a panel of early hematopoietic genes in the ICM of 20 to 24 hpf fish by whole mount in situ hybridization (WISH). There was an overall reduction in the expression of lmo2, scl, gata-1 and gata-2. Upon closer observation it was apparent that the reduction was due to the loss of certain cells from the ICM with normal staining intensity in the remaining cells. We also observed reduced cyclin D1 expression and elevated caspase 3 activity, which strongly suggested programmed cell death was activated in the jak2a morphant. We believe that there is a selective loss due to cell cycle arrest of the more mature hematopoietic cells, which require the expression of jak2a for their survival with retention of early hematopoietic progenitors and hematopoietic stem cells in the ICM. These observations in developing zebrafish embryos establish the important role of jak2a in hematopoiesis and provide new insights into the stage of hematopoiesis where jak2a is critically important.
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Bolli, Niccolò, Elspeth M. Payne, Jennifer Rhodes, Evisa Gjini, Adam B. Johnston, Feng Guo, Jeong-Soo Lee i in. "cpsf1 is required for definitive HSC survival in zebrafish". Blood 117, nr 15 (14.04.2011): 3996–4007. http://dx.doi.org/10.1182/blood-2010-08-304030.
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Abstract A comprehensive understanding of the genes and pathways regulating hematopoiesis is needed to identify genes causally related to bone marrow failure syndromes, myelodysplastic syndromes, and hematopoietic neoplasms. To identify novel genes involved in hematopoiesis, we performed an ethyl-nitrosourea mutagenesis screen in zebrafish (Danio rerio) to search for mutants with defective definitive hematopoiesis. We report the recovery and analysis of the grechetto mutant, which harbors an inactivating mutation in cleavage and polyadenylation specificity factor 1 (cpsf1), a gene ubiquitously expressed and required for 3′ untranslated region processing of a subset of pre-mRNAs. grechetto mutants undergo normal primitive hematopoiesis and specify appropriate numbers of definitive HSCs at 36 hours postfertilization. However, when HSCs migrate to the caudal hematopoietic tissue at 3 days postfertilization, their numbers start decreasing as a result of apoptotic cell death. Consistent with Cpsf1 function, c-myb:EGFP+ cells in grechetto mutants also show defective polyadenylation of snrnp70, a gene required for HSC development. By 5 days postfertilization, definitive hematopoiesis is compromised and severely decreased blood cell numbers are observed across the myeloid, erythroid, and lymphoid cell lineages. These studies show that cpsf1 is essential for HSC survival and differentiation in caudal hematopoietic tissue.
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Canu, Giovanni, i Christiana Ruhrberg. "First blood: the endothelial origins of hematopoietic progenitors". Angiogenesis 24, nr 2 (30.03.2021): 199–211. http://dx.doi.org/10.1007/s10456-021-09783-9.
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AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.
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Jin, Hao, Jin Xu i Zilong Wen. "Migratory path of definitive hematopoietic stem/progenitor cells during zebrafish development". Blood 109, nr 12 (15.06.2007): 5208–14. http://dx.doi.org/10.1182/blood-2007-01-069005.
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Abstract The development of vertebrate definitive hematopoiesis is featured by temporally and spatially dynamic distribution of hematopoietic stem/progenitor cells (HSPCs). It is proposed that the migration of definitive HSPCs, at least in part, accounts for this unique characteristic; however, compelling in vivo lineage evidence is still lacking. Here we present an in vivo analysis to delineate the migration route of definitive HSPCs in the early zebrafish embryo. Cell-marking analysis was able to first map definitive HSPCs to the ventral wall of dorsal aorta (DA). These cells were subsequently found to migrate to a previously unappreciated organ, posterior blood island (PBI), located between the caudal artery and caudal vein, and finally populate the kidney, the adult hematopoietic organ. These findings demonstrate that the PBI acts as an intermediate hematopoietic organ in a manner analogous to the mammalian fetal liver to sustain definitive hematopoiesis before adult kidney hematopoiesis occurs. Thus our study unambiguously documents the in vivo trafficking of definitive HSPCs among developmentally successive hematopoietic compartments and underscores the ontogenic conservation of definitive hematopoiesis between zebrafish and mammals.
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Lin, Kuan-Hung, Jui-Chung Chiang, Ya-Hsuan Ho, Chao-Ling Yao i Hsinyu Lee. "Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling". International Journal of Molecular Sciences 21, nr 6 (16.03.2020): 2015. http://dx.doi.org/10.3390/ijms21062015.
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Vertebrate hematopoiesis is a complex physiological process that is tightly regulated by intracellular signaling and extracellular microenvironment. In recent decades, breakthroughs in lineage-tracing technologies and lipidomics have revealed the existence of numerous lipid molecules in hematopoietic microenvironment. Lysophosphatidic acid (LPA), a bioactive phospholipid molecule, is one of the identified lipids that participates in hematopoiesis. LPA exhibits various physiological functions through activation of G-protein-coupled receptors. The functions of these LPARs have been widely studied in stem cells, while the roles of LPARs in hematopoietic stem cells have rarely been examined. Nonetheless, mounting evidence supports the importance of the LPA-LPAR axis in hematopoiesis. In this article, we have reviewed regulation of hematopoiesis in general and focused on the microenvironmental and intracellular effects of the LPA in hematopoiesis. Discoveries in these areas may be beneficial to our understanding of blood-related disorders, especially in the context of prevention and therapy for anemia.
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Lim, Hong Kiat, Pravin Periasamy i Helen C. O’Neill. "In Vitro Murine Hematopoiesis Supported by Signaling from a Splenic Stromal Cell Line". Stem Cells International 2018 (25.12.2018): 1–9. http://dx.doi.org/10.1155/2018/9896142.
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There are very few model systems which demonstrate hematopoiesis in vitro. Previously, we described unique splenic stromal cell lines which support the in vitro development of hematopoietic cells and particularly myeloid cells. Here, the 5G3 spleen stromal cell line has been investigated for capacity to support the differentiation of hematopoietic cells from progenitors in vitro. Initially, 5G3 was shown to express markers of mesenchymal but not endothelial or hematopoietic cells and to resemble perivascular reticular cells in the bone marrow through gene expression. In particular, 5G3 resembles CXCL12-abundant reticular cells or perivascular reticular cells, which are important niche elements for hematopoiesis in the bone marrow. To analyse the hematopoietic support function of 5G3, specific signaling pathway inhibitors were tested for the ability to regulate cell production in vitro in cocultures of stroma overlaid with bone marrow-derived hematopoietic stem/progenitor cells. These studies identified an important role for Wnt and Notch pathways as well as tyrosine kinase receptors like c-KIT and PDGFR. Cell production in stromal cocultures constitutes hematopoiesis, since signaling pathways provided by splenic stroma reflect those which support hematopoiesis in the bone marrow.
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Migliaccio, Anna Rita, Fabrizio Martelli, Maria Verrucci, Massimo Sanchez, Mauro Valeri, Giovanni Migliaccio, Alessandro Maria Vannucchi i in. "Gata1 expression driven by the alternative HS2 enhancer in the spleen rescues the hematopoietic failure induced by the hypomorphic Gata1low mutation". Blood 114, nr 10 (3.09.2009): 2107–20. http://dx.doi.org/10.1182/blood-2009-03-211680.
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Abstract Rigorously defined reconstitution assays developed in recent years have allowed recognition of the delicate relationship that exists between hematopoietic stem cells and their niches. This balance ensures that hematopoiesis occurs in the marrow under steady-state conditions. However, during development, recovery from hematopoietic stress and in myeloproliferative disorders, hematopoiesis occurs in extramedullary sites whose microenvironments are still poorly defined. The hypomorphic Gata1low mutation deletes the regulatory sequences of the gene necessary for its expression in hematopoietic cells generated in the marrow. By analyzing the mechanism that rescues hematopoiesis in mice carrying this mutation, we provide evidence that extramedullary microenvironments sustain maturation of stem cells that would be otherwise incapable of maturing in the marrow.
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Kashlakova, A. I., B. V. Biderman i E. N. Parovichnikova. "Clonal hematopoiesis and acute myeloid leukemia". Oncohematology 18, nr 3 (12.09.2023): 92–101. http://dx.doi.org/10.17650/1818-8346-2023-18-3-92-101.
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During aging phenotypic changes in the hematopoietic system occur, and possible reason of these changes can be accumulation of gene mutations in hematopoietic stem cells or early blood progenitors. Although these mutations are mostly neutral, some may give hematopoietic stem cells and progenitor cells a proliferative advantage. In this case clonal hematopoiesis will arise, which is characterized by the formation of a genetically distinct subpopulation of blood cells. Clonal hematopoiesis may become a basis for the development of hematologic malignancies, such as acute myeloid leukemia. Clonal hematopoiesis associated genes which are most commonly mutated in acute myeloid leukemia patients are DNMT3A, TET2 and ASXL1. The prognostic significance of these gene mutations currently remains a subject of study.
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Yamane, Toshiyuki. "Cellular Basis of Embryonic Hematopoiesis and Its Implications in Prenatal Erythropoiesis". International Journal of Molecular Sciences 21, nr 24 (8.12.2020): 9346. http://dx.doi.org/10.3390/ijms21249346.
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Primitive erythrocytes are the first hematopoietic cells observed during ontogeny and are produced specifically in the yolk sac. Primitive erythrocytes express distinct hemoglobins compared with adult erythrocytes and circulate in the blood in the nucleated form. Hematopoietic stem cells produce adult-type (so-called definitive) erythrocytes. However, hematopoietic stem cells do not appear until the late embryonic/early fetal stage. Recent studies have shown that diverse types of hematopoietic progenitors are present in the yolk sac as well as primitive erythroblasts. Multipotent hematopoietic progenitors that arose in the yolk sac before hematopoietic stem cells emerged likely fill the gap between primitive erythropoiesis and hematopoietic stem-cell-originated definitive erythropoiesis and hematopoiesis. In this review, we discuss the cellular origin of primitive erythropoiesis in the yolk sac and definitive hematopoiesis in the fetal liver. We also describe mechanisms for developmental switches that occur during embryonic and fetal erythropoiesis and hematopoiesis, particularly focusing on recent studies performed in mice.
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Kieusseian, Aurélie, Jalila Chagraoui, Cécile Kerdudo, Philippe-Emmanuel Mangeot, Philip J. Gage, Nicole Navarro, Brigitte Izac, Georges Uzan, Bernard G. Forget i Anne Dubart-Kupperschmitt. "Expression of Pitx2 in stromal cells is required for normal hematopoiesis". Blood 107, nr 2 (15.01.2006): 492–500. http://dx.doi.org/10.1182/blood-2005-02-0529.
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AbstractAlthough the expression of Pitx2, a bicoid family homeodomain transcription factor, is highly regulated during hematopoiesis, its function during this process was not documented; we thus studied hematopoiesis in Pitx2-null mice. We found that Pitx2–/– embryos display hypoplastic livers with reduced numbers of hematopoietic cells, but these cells had normal hematopoietic potential, as evidenced by colony-forming assays, immature progenitor cell assays, and long-term repopulation assays. Because the microenvironment is also crucial to the development of normal hematopoiesis, we established Pitx2–/– and Pitx2+/+ stromas from fetal liver and studied their hematopoietic supportive capacity. We showed that the frequency of cobblestone area-forming cells was 4-fold decreased when using Pitx2–/– stromal cells compared with Pitx2+/+ stromal cells, whatever the Pitx2 genotype of hematopoietic cells tested in this assay. This defect was rescued by expression of Pitx2 into Pitx2–/– fetal liver stromal cells, demonstrating a major and direct role of Pitx2 in the hematopoietic supportive capacity of fetal liver stroma. Finally, we showed a reduced capacity of MS5 stromal cells expressing Pitx2 RNAi to support human hematopoiesis. Altogether these data showed that Pitx2 has major functions in the hematopoietic supportive capacity of fetal liver and adult bone marrow stromal cells.
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Zambidis, Elias T., Jihan Osborne i Curt I. Civin. "Generation of a Common Progenitor Population from Human Embryonic Stem Cells That Gives Rise to Both Embryonic Erythropoiesis and Definitive Hematopoiesis." Blood 106, nr 11 (16.11.2005): 521. http://dx.doi.org/10.1182/blood.v106.11.521.521.
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Abstract Human embryonic stem cells (hESC) provide a valuable new tool for dissecting the earliest developmental events of human hematopoietic-stem progenitor cell (HSPC) genesis. We have recently reported the efficient step-wise differentiation of hESC to embryonic (primitive) erythroid cells followed by definitive erythro-myeloid hematopoietic cells from human embryoid bodies (hEB). Hematopoiesis proceeds spontaneously from hEB-derived cells and appears to model the earliest events of embryonic and definitive hematopoiesis in a manner resembling human yolk sac development. We now extend our studies to define conditions which may favor differentiation into definitive hematopoietic cells from hEB. We previously demonstrated that hEB-derived primitive hematopoiesis requires fetal calf serum, but proceeds in the absence of supplemented recombinant growth factors to developing hEB’s. We now show that supplementing hEB differentiation cultures with a broad array of hematopoietic growth factors dramatically enhances the number of primitive erythroblasts, definitive myeloid, BFU-E, CFU-E, and multi-potent mixed colonies in methylcellulose CFC assays while not affecting the kinetics of hematopoietic differentiation. The inclusion of VEGF-165 during hEB differentiation was found to have an exceptionally potent effect in increasing the multilineage generation of both primitive and definitive hEB-derived hematopoietic cells. To further define the hEB-derived population which gives rise to primitive and definitive hematopoiesis we FACS-purified a population of CD45-CD31+CD34+ hEB cells which we and others have shown are capable of both endothelial and hematogenous differentiation. Co-culture of this purified population in serum-containing OP9 stromal layers gave rise primarily to definitive-type erythro-myeloid cells including mature beta-globin-expressing erythroid cells, neutrophils, monocytes/macrophages, CD41+ megakaryocyte precursors, and CD56+ NK-like cells. Alternative culture of this purified CD45-CD31+CD34+ hEB population in serum-free, stromal-free cultures supplemented with erythropoietin and VEGF-165 produced an abundant population of embryonic (nucleated gamma, epsilon, zeta chain-hemoglobin-expressing) erythroblasts. To isolate a clonogenic, expandable human hemangioblastic progenitor of primitive and definitive hematopoieisis as well as endothelial cells in our system, we have prepared transgenic hESC lines expressing a GFP reporter cDNA under the hemato-endothelial regulatory sequences of the human genomic SCL/TAL1 locus. Our hESC model reveals, for the first time, the putative existence of a population of human hEB progenitors capable of both embryonic-type and definitive blood cells depending on the differentiation environment.
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Imamura, Masahiro. "Impaired Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation: Its Pathogenesis and Potential Treatments". Hemato 2, nr 1 (2.01.2021): 43–63. http://dx.doi.org/10.3390/hemato2010002.
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Impaired hematopoiesis is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Bone marrow aplasia and peripheral cytopenias arise from primary and secondary graft failure or primary and secondary poor graft function. Chimerism analysis is useful to discriminate these conditions. By determining the pathogenesis of impaired hematopoiesis, a timely and appropriate treatment can be performed. Hematopoietic system principally consists of hematopoietic stem cells and bone marrow microenvironment termed niches. Abnormality in hematopoietic stem and progenitor cells and/or abnormality in the relevant niches give rise to hematological diseases. Allo-HSCT is intended to cure each hematological disease, replacing abnormal hematopoietic stem cells and bone marrow niches with hematopoietic stem cells and bone marrow niches derived from normal donors. Therefore, treatment for graft failure and poor graft function after allo-HSCT is required to proceed based on determining the pathogenesis of impaired hematopoiesis. Recent progress in this area suggests promising treatment manipulations for graft failure and poor graft function.
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Li, Xiang, Shunji Jia, Shaohe Wang, Yuemeng Wang i Anming Meng. "Mta3-NuRD complex is a master regulator for initiation of primitive hematopoiesis in vertebrate embryos". Blood 114, nr 27 (24.12.2009): 5464–72. http://dx.doi.org/10.1182/blood-2009-06-227777.
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Abstract Metastasis-associated antigens 1/2/3 (Mta1/2/3) are components of nucleosome remodeling and deacetylase (NuRD) complexes and have been found to play roles in embryonic development and homeostasis. However, their functions in primitive hematopoiesis are unknown. In this study, we demonstrate that knockdown of mta3 by antisense morpholinos abolishes primitive hematopoietic lineages and causes abnormal angiogenesis in zebrafish embryos. However, the expression of the pronephric duct and paraxial mesoderm markers is unaltered and the specification of angioblasts is unaffected in mta3 morphants. The results suggest that mta3 is specifically required for primitive hematopoiesis. Furthermore, inhibition of deacetylase activity with the inhibitors valproic acid (VPA) or trichostatin A (TSA) in zebrafish embryos completely blocks primitive hematopoiesis, resulting in hematopoietic defects almost identical to those seen in mta3 morphants. Importantly, overexpression of scl or scl and lmo2, 2 master genes for primitive hematopoiesis, is able to overturn effects of mta3 knockdown or VPA/TSA treatment; and overexpression of mta3, and human MBD3 or HDAC1, 2 other components of NuRD complex, enhances the expression of scl and lmo2 in the posterior lateral plate mesoderm during early primitive hematopoiesis. We conclude that Mta3-NuRD complex is essential for the initiation of primitive hematopoiesis. Thus, our findings provide new insight into the regulatory hierarchy of primitive hematopoiesis in vertebrates.
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Visnjic, Dora, Zana Kalajzic, David W. Rowe, Vedran Katavic, Joseph Lorenzo i Hector L. Aguila. "Hematopoiesis is severely altered in mice with an induced osteoblast deficiency". Blood 103, nr 9 (1.05.2004): 3258–64. http://dx.doi.org/10.1182/blood-2003-11-4011.
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Abstract We previously reported a transgenic mouse model expressing herpesvirus thymidine kinase (TK) gene under the control of a 2.3-kilobase fragment of the rat collagen α1 type I promoter (Col2.3ΔTK). This construct confers lineage-specific expression in developing osteoblasts, allowing the conditional ablation of osteoblast lineage after treatment with ganciclovir (GCV). After GCV treatment these mice have profound alterations on bone formation leading to a progressive bone loss. In addition, treated animals also lose bone marrow cellularity. In this report we characterized hematopoietic parameters in GCV-treated Col2.3ΔTK mice, and we show that after treatment transgenic animals lose lymphoid, erythroid, and myeloid progenitors in the bone marrow, followed by decreases in the number of hematopoietic stem cells (HSCs). Together with the decrease in bone marrow hematopoiesis, active extramedullary hematopoiesis was observed in the spleen and liver, as measured by an increase in peripheral HSCs and active primary in vitro hematopoiesis. After withdrawal of GCV, osteoblasts reappeared in the bone compartment together with a recovery of medullary and decrease in extramedullary hematopoiesis. These observations directly demonstrate the role of osteoblasts in hematopoiesis and provide a model to study the interactions between the mesenchymal and hematopoietic compartments in the marrow. (Blood. 2004; 103:3258-3264)
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Fujita, Satoshi, Junya Toguchida, Yutaka Morita i Hiroo Iwata. "Clonal Analysis of Hematopoiesis-Supporting Activity of Human Mesenchymal Stem Cells in Association with Jagged1 Expression and Osteogenic Potential". Cell Transplantation 17, nr 10-11 (październik 2008): 1169–79. http://dx.doi.org/10.3727/096368908787236611.
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Human mesenchymal stem cells (hMSCs) are promising feeder cells for expanding hematopoietic stem cells (HSCs), but their potential is heterogeneous. We examined the hematopoiesis-supporting activity of hMSC at the clonal level in relation to the osteogenic potential and gene expression. Hematopoiesis-supporting activities of stably immortalized clonal hMSC lines were evaluated by the expansion of CD34+CD38- cells after 7-day coculture with human cord blood-derived CD34+ cells. Six of 16 clones expanded the numbers of CD34+CD38- cells >500-fold. These hematopoiesis-supportive clones also showed high gene expression of Jagged1, a Notch ligand, as well as high potential to deposit calcium after osteogenic induction. Thus, osteogenic hMSC clones may provide proper microenvironments for HSC expansion, ultimately conveying self-renewal signals to HSCs via the Notch pathway. However, they lost hematopoiesis-supporting activity after osteogenic differentiation. The hematopoiesis-supportive clones are potentially useful for hematopoietic microenvironment studies and as components of a coculture system for expansion of HSCs, free from contamination by xenogeneic pathogens.
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Petinati, N. A., i N. J. Drize. "Clonal hematopoiesis and its role in the development of hematological diseases". Russian journal of hematology and transfusiology 66, nr 4 (1.12.2021): 580–92. http://dx.doi.org/10.35754/0234-5730-2021-66-4-580-592.
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Introduction. The formation of blood cells in a healthy individual is ensured by polyclonal hematopoiesis. Recent studies have shown that with age, large clones with a common genetic marker are found in the peripheral blood, i. e. cells originating from a single progenitor cell. This phenomenon is called clonal hematopoiesis. In some cases, people with clonal hematopoiesis develop hematological diseases.Aim — to describe and summarize current data on the relationship between clonal hematopoiesis and hematological diseases.Main findings. This review describes the history of detection of clonal hematopoiesis, its main properties, the most frequent mutations in hematopoietic clones associated with the risk of transformation into myelodysplastic syndrome, and acute myeloid leukemia. The meaning and possible pathogenesis of tumor transformation are discussed.
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Tague, Laneshia, Karolyn A. Oetjen, Anirudh Mahadev, Daniel C. Link i Andrew E. Gelman. "Increased Incidence of Clonal Hematopoiesis in Lung Transplant Recipients Involves DNA Damage Response Genes". Blood 138, Supplement 1 (5.11.2021): 2163. http://dx.doi.org/10.1182/blood-2021-150674.
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Abstract Lung transplant recipients receive lifelong immunosuppression that includes a calcineurin inhibitor (tacrolimus or cyclosporine), an anti-proliferative agent (mycophenolate or azathioprine) and corticosteroids. They are also known to be at increased risk for a broad spectrum of adverse hematologic events. This includes relatively common complications such as neutropenia and other cytopenias, which occur in over half of patients, as well as rarer events such as de novo hematopoietic malignancy. Certain patterns of clonal hematopoiesis, the expansion of unique somatic clones in hematopoietic stem cells, are known to be associated with cytotoxic therapy and the development of hematologic malignancies. We hypothesized that the stress of transplantation and subsequent immunosuppression provides an environment whereby a unique pattern of clonal hematopoiesis emerges. To evaluate this hypothesis, we designed a custom panel of 59 genes using an error-corrected sequencing assay capable of detecting variant allele frequency (VAF) as low as 0.01. We characterized the overall burden and distribution of clonal hematopoiesis and compared differences among lung transplant recipients (n=73) and age-matched healthy controls (n=19). Clonal hematopoiesis was identified in 51/73 (69.9%) of lung transplant recipients. This was significantly higher than the frequency in the age-matched healthy controls (6/19,31.6% p=0.0071). Additionally, 27/51 (52.9%) of patients with clonal hematopoiesis had multiple variants. The increase in clonal hematopoiesis was mainly due to mutations in DNA damage response (DDR) genes (ATM, PPM1D, SRCAP or TP53), with 29/73 (39.7%) of lung transplant recipients carrying one or more mutation compared with 1/19 (5.3%) of age-matched healthy controls (5.3%, p=0.029). No significant difference in the frequency of clonal hematopoiesis due to non-DDR genes was also observed (48% vs. 26.3%, p=0.121). We first evaluated the relationship between clonal hematopoiesis and lung transplant indication. This is relevant, since interstitial lung disease (ILD), a common indication for lung transplantation, is associated with telomeropathies which are also linked to bone marrow failure and clonal hematopoiesis. However, the frequency of DDR clonal hematopoiesis in ILD patients (17/39, 44%) was similar to that observed in patients with COPD (9/20, 45%). We next investigated the association of immunosuppression with clonal hematopoiesis. Overall, 30/48 patients on mycophenolate (MPA) and 13/19 patients on azathioprine (AZA) had at least 1 clonal hematopoiesis mutation. We found no significant difference in overall clonal hematopoiesis frequency among patients on MPA vs. AZA. However, the frequency of DDR clonal hematopoiesis was significantly higher in patients on AZA (OR 4.04, 95% CI 1.22-13.38, p=0.022) than in patients on MPA. Moreover, when we assessed clonal hematopoiesis burden via Poisson regression, it was increased in patients receiving AZA (1.68, 95% CI 1.08-2.59, p=0.020) when compared to patients on MPA. All lung transplant recipients were maintained on tacrolimus but one, so associations with type of calcineurin inhibitor could not be assessed. Finally, we assessed clonal hematopoiesis in recipients who developed neutropenia (n=24) and found no significant association. To the best of our knowledge, we report the first evidence of increased clonal hematopoiesis in a solid organ transplant population. Our data indicate that azathioprine therapy is associated with the expansion of hematopoietic clones carrying variants in DDR genes. However, azathioprine therapy often represents a failure of MPA therapy, typically due to either hematologic or gastrointestinal toxicity. Therefore, the association noted might reflect MPA intolerance rather than azathioprine therapy. Nevertheless, prior studies show that treatment with genotoxic agents, such as chemotherapy or radiation therapy, provide a fitness advantage to hematopoietic stem/progenitor cells carrying DDR gene variants. Whether azathioprine vs. MPA therapy confers a similar fitness advantage is currently under investigation. Further investigation also is warranted to determine if the presence of clonal hematopoiesis influences lung transplant outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Chung, Stephen S., i Christopher Y. Park. "Aging, hematopoiesis, and the myelodysplastic syndromes". Blood Advances 1, nr 26 (8.12.2017): 2572–78. http://dx.doi.org/10.1182/bloodadvances.2017009852.
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Abstract The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.