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Journal articles on the topic 'Epithelium Cell differentiation'
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1
Levine, J. F., and F. E. Stockdale. "Cell-cell interactions promote mammary epithelial cell differentiation." Journal of Cell Biology 100, no. 5 (1985): 1415–22. http://dx.doi.org/10.1083/jcb.100.5.1415.
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Mammary epithelium differentiates in a stromal milieu of adipocytes and fibroblasts. To investigate cell-cell interactions that may influence mammary epithelial cell differentiation, we developed a co-culture system of murine mammary epithelium and adipocytes and other fibroblasts. Insofar as caseins are specific molecular markers of mammary epithelial differentiation, rat anti-mouse casein monoclonal antibodies were raised against the three major mouse casein components to study this interaction. Mammary epithelium from mid-pregnant mice was plated on confluent irradiated monolayers of 3T3-L1 cells, a subclone of the Swiss 3T3 cell line that differentiates into adipocytes in monolayer culture and other cell monolayers (3T3-C2 cells, Swiss 3T3 cells, and human foreskin fibroblasts). Casein was synthesized by mammary epithelium only in the presence of co-cultured cells and the lactogenic hormone combination of insulin, hydrocortisone, and prolactin. Synthesis and accumulation of alpha-, beta-, and gamma-mouse casein within the epithelium was shown by immunohistochemical staining of cultured cells with anti-casein monoclonal antibodies, and the specificity of the immunohistochemical reaction was demonstrated using immunoblots. A competitive immunoassay was used to measure the amount of casein secreted into the culture medium. In a 24-h period, mammary epithelium co-cultured with 3T3-L1 cells secreted 12-20 micrograms beta-casein per culture dish. There was evidence of specificity in the cell-cell interaction that mediates hormone-dependent casein synthesis. Swiss 3T3 cells, newborn foreskin fibroblasts, substrate-attached material ("extracellular matrix"), and tissue culture plastic did not support casein synthesis, whereas monolayers of 3T3-L1 and 3T3-C2 cells, a subclone of Swiss 3T3 cells that does not undergo adipocyte differentiation, did. We conclude that interaction between mammary epithelium and other specific nonepithelial cells markedly influences the acquisition of hormone sensitivity of the epithelium and hormone-dependent differentiation.
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Yang, Honghua, Min Min Lu, Lili Zhang, Jeffrey A. Whitsett, and Edward E. Morrisey. "GATA6 regulates differentiation of distal lung epithelium." Development 129, no. 9 (2002): 2233–46. http://dx.doi.org/10.1242/dev.129.9.2233.
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GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal epithelium of the lung during development. To define the role that GATA6 plays during lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal lung epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.
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Vermeer, Paola D., Lacey Panko, Philip Karp, John H. Lee, and Joseph Zabner. "Differentiation of human airway epithelia is dependent on erbB2." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 2 (2006): L175—L180. http://dx.doi.org/10.1152/ajplung.00547.2005.
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A clinical case documented a reversible change in airway epithelial differentiation that coincided with the initiation and discontinuation of trastuzumab, an anti-erbB2 antibody. This prompted the investigation into whether blocking the erbB2 receptor alters differentiation of the airway epithelium. To test this hypothesis, we treated an in vitro model of well-differentiated human airway epithelia with trastuzumab or heregulin-α, an erbB ligand. In addition, coculturing with human lung fibroblasts tested whether in vivo subepithelial fibroblasts function as an endogenous source of ligands able to activate erbB receptors expressed by the overlying epithelial cells. Epithelia were stained with hematoxylin and eosin and used for morphometric analysis. Trastuzumab treatment decreased the ciliated cell number by 49% and increased the metaplastic, flat cell number by 640%. Heregulin-α treatment increased epithelial height and decreased the number of metaplastic and nonciliated columnar cells, whereas it increased the goblet cell number. We found that normal human lung fibroblasts express transforming growth factor-α, heparin-binding epidermal-like growth factor, epiregulin, heregulin-α, and amphiregulin, all of which are erbB ligands. Cocultures of airway epithelia with primary fibroblasts increased epithelial height comparable to that achieved following heregulin-α treatment. These data show that erbB2 stimulation is required for maintaining epithelial differentiation. Furthermore, the mesenchyme underlying the airway epithelium secretes a variety of erbB ligands that may direct various pathways of epithelial differentiation.
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Miyagawa, Shinichi, and Taisen Iguchi. "Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina." Proceedings of the National Academy of Sciences 112, no. 42 (2015): 12986–91. http://dx.doi.org/10.1073/pnas.1513550112.
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Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epithelium-specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs.
5
Gerbe, François, Johan H. van Es, Leila Makrini, et al. "Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium." Journal of Cell Biology 192, no. 5 (2011): 767–80. http://dx.doi.org/10.1083/jcb.201010127.
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The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous identification. We demonstrate that although mature tuft cells express DCLK1, a putative marker of quiescent stem cells, they are post-mitotic, short lived, derive from Lgr5-expressing epithelial stem cells, and are found in mouse and human tumors. We show that whereas the ATOH1/MATH1 transcription factor is essential for their differentiation, Neurog3, SOX9, GFI1, and SPDEF are dispensable, which distinguishes these cells from enteroendocrine, Paneth, and goblet cells, and raises from three to four the number of secretory cell types in the intestinal epithelium. Moreover, we show that tuft cells are the main source of endogenous intestinal opioids and are the only epithelial cells that express cyclooxygenase enzymes, suggesting important roles for these cells in the intestinal epithelium physiopathology.
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Smiley-Jewell, Suzette M., Susan J. Nishio, Alison J. Weir, and Charles G. Plopper. "Neonatal Clara cell toxicity by 4-ipomeanol alters bronchiolar organization in adult rabbits." American Journal of Physiology-Lung Cellular and Molecular Physiology 274, no. 4 (1998): L485—L498. http://dx.doi.org/10.1152/ajplung.1998.274.4.l485.
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Nonciliated bronchiolar (Clara) cells metabolize environmental toxicants, are progenitor cells during development, and differentiate postnatally. Because differentiating Clara cells of neonatal rabbits are injured at lower doses by the cytochrome P-450-activated cytotoxicant 4-ipomeanol than are those of adults, the impact of early injury on the bronchiolar epithelial organization of adults was defined by treating neonates (3–21 days) and examining them at 4–6 wk. Bronchiolar epithelium of 6-wk-old animals treated on day 7 was most altered from that of control animals. Almost 100% of the bronchioles were lined by zones of squamous epithelial cells. Compared with control animals, the distal bronchiolar epithelium of 4-ipomeanol-treated animals had more squamous cells (70–90 vs. 0%) with a reduced overall epithelial thickness (25% of control value), fewer ciliated cells (0 vs. 10–20%), a reduced expression of Clara cell markers of differentiation (cytochrome P-4502B, NADPH reductase, and 10-kDa protein), and undifferentiated nonciliated cuboidal cell ultrastructure. We conclude that early injury to differentiating rabbit Clara cells by a cytochrome P-450-mediated toxicant inhibits bronchiolar epithelial differentiation and greatly affects repair.
7
Cui, Yongzhi, Greg Riedlinger, Keiko Miyoshi, et al. "Inactivation of Stat5 in Mouse Mammary Epithelium during Pregnancy Reveals Distinct Functions in Cell Proliferation, Survival, and Differentiation." Molecular and Cellular Biology 24, no. 18 (2004): 8037–47. http://dx.doi.org/10.1128/mcb.24.18.8037-8047.2004.
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ABSTRACT This study explored the functions of the signal transducers and activators of transcription 5a and 5b (referred to as Stat5 here) during different stages of mouse mammary gland development by using conditional gene inactivation. Mammary gland morphogenesis includes cell specification, proliferation and differentiation during pregnancy, cell survival and maintenance of differentiation throughout lactation, and cell death during involution. Stat5 is activated by prolactin, and its presence is mandatory for the proliferation and differentiation of mammary epithelium during pregnancy. To address the question of whether Stat5 is also necessary for the maintenance and survival of the differentiated epithelium, the two genes were deleted at different time points. The 110-kb Stat5 locus in the mouse was bracketed with loxP sites, and its deletion was accomplished by using two Cre-expressing transgenic lines. Loss of Stat5 prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after mammary epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that at this stage epithelial cell proliferation, differentiation, and survival require Stat5.
8
Caniggia, I., I. Tseu, R. N. Han, B. T. Smith, K. Tanswell, and M. Post. "Spatial and temporal differences in fibroblast behavior in fetal rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 261, no. 6 (1991): L424—L433. http://dx.doi.org/10.1152/ajplung.1991.261.6.l424.
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Fibroblast-epithelial interactions were investigated in cells from late-gestation fetal rat lung. Fibroblasts from the pseudoglandular stage of lung development stimulated epithelial cell proliferation, whereas fibroblasts from the saccular stage promoted epithelial cell differentiation. The developmental switch from proliferation to differentiation seemed to be controlled by both cell types. Fibroblast-derived epithelial cell growth-promoting activity, evident in cells from the pseudoglandular period, decreased during development and almost disappeared in cells from the saccular stage. Interestingly, the response of epithelial cells to this growth-promoting activity declined with advancing gestational age as epithelial cells became more responsive to fibroblast-derived differentiation factor(s). Production of differentiation factor(s) by fibroblasts increased during the canalicular stage of lung development. Platelet-derived growth factor (PDGF) and low concentrations of transforming growth factor-beta (TGF-beta) stimulated epithelial cell proliferation. PDGF did not affect differentiation, whereas TGF-beta was inhibitory. Dependent on their proximity to the epithelium, two subpopulations of fibroblasts that differed in their ability to promote epithelial cell proliferation or differentiation were isolated. Fibroblasts in close proximity to the epithelium mainly produced differentiation factors, whereas more distant fibroblasts primarily stimulated proliferation.
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Fukumoto, Satoshi, Takayoshi Kiba, Bradford Hall, et al. "Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts." Journal of Cell Biology 167, no. 5 (2004): 973–83. http://dx.doi.org/10.1083/jcb.200409077.
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Tooth morphogenesis results from reciprocal interactions between oral epithelium and ectomesenchyme culminating in the formation of mineralized tissues, enamel, and dentin. During this process, epithelial cells differentiate into enamel-secreting ameloblasts. Ameloblastin, an enamel matrix protein, is expressed by differentiating ameloblasts. Here, we report the creation of ameloblastin-null mice, which developed severe enamel hypoplasia. In mutant tooth, the dental epithelium differentiated into enamel-secreting ameloblasts, but the cells were detached from the matrix and subsequently lost cell polarity, resumed proliferation, and formed multicell layers. Expression of Msx2, p27, and p75 were deregulated in mutant ameloblasts, the phenotypes of which were reversed to undifferentiated epithelium. We found that recombinant ameloblastin adhered specifically to ameloblasts and inhibited cell proliferation. The mutant mice developed an odontogenic tumor of dental epithelium origin. Thus, ameloblastin is a cell adhesion molecule essential for amelogenesis, and it plays a role in maintaining the differentiation state of secretory stage ameloblasts by binding to ameloblasts and inhibiting proliferation.
10
Gao, Xia, Aman S. Bali, Scott H. Randell, and Brigid L. M. Hogan. "GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells." Journal of Cell Biology 211, no. 3 (2015): 669–82. http://dx.doi.org/10.1083/jcb.201506014.
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Pseudostratified airway epithelium of the lung is composed of polarized ciliated and secretory cells maintained by basal stem/progenitor cells. An important question is how lineage choice and differentiation are coordinated with apical–basal polarity and epithelial morphogenesis. Our previous studies indicated a key integrative role for the transcription factor Grainyhead-like 2 (Grhl2). In this study, we present further evidence for this model using conditional gene deletion during the regeneration of airway epithelium and clonal organoid culture. We also use CRISPR/Cas9 genome editing in primary human basal cells differentiating into organoids and mucociliary epithelium in vitro. Loss of Grhl2 inhibits organoid morphogenesis and the differentiation of ciliated cells and reduces the expression of both notch and ciliogenesis genes (Mcidas, Rfx2, and Myb) with distinct Grhl2 regulatory sites. The genome editing of other putative target genes reveals roles for zinc finger transcription factor Znf750 and small membrane adhesion glycoprotein in promoting ciliogenesis and barrier function as part of a network of genes coordinately regulated by Grhl2.
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Stappenbeck, T. S., and J. I. Gordon. "Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine." Development 127, no. 12 (2000): 2629–42. http://dx.doi.org/10.1242/dev.127.12.2629.
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The mouse small intestinal epithelium undergoes continuous renewal throughout life. Previous studies suggest that differentiation of this epithelium is regulated by instructions that are received as cells migrate along crypt-villus units. The nature of the instructions and their intracellular processing remain largely undefined. In this report, we have used genetic mosaic analysis to examine the role of Rac1 GTPase-mediated signaling in controlling differentiation. A constitutively active mutation (Rac1Leu61) or a dominant negative mutation (Rac1Asn17) was expressed in the 129/Sv embryonic stem cell-derived component of the small intestine of C57Bl/6-ROSA26<->129/Sv mice. Rac1Leu61 induces precocious differentiation of members of the Paneth cell and enterocytic lineages in the proliferative compartment of the fetal gut, without suppressing cell division. Forced expression of the dominant negative mutation inhibits epithelial differentiation, without affecting cell division, and slows enterocytic migration along crypt-villus units. The effects produced by Rac1Leu61 or Rac1Asn17 in the 129/Sv epithelium do not spread to adjacent normal C57Bl/6 epithelial cells. These results provide in vivo evidence that Rac1 is involved in the import and intracellular processing of signals that control differentiation of a mammalian epithelium.
12
Dabelsteen, Erik, Ulla Mandel, and Henrik Clausen. "Cell Surface Carbohydrates Are Markers of Differentiation in Human Oral Epithelium." Critical Reviews in Oral Biology & Medicine 2, no. 4 (1991): 493–507. http://dx.doi.org/10.1177/10454411910020040301.
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Carbohydrates of the epithelial cell membrane are involved in cell-cell and cell-substrate interaction, and changes are seen in relationship to cell differentiation and neoplastic transformation. The terminal part of carbohydrate structures carried on oral epithelial cells often expresses antigens of the ABO and Lewis blood group systems. The expression of these antigens are in oral mucosa genetically regulated by the A, B, H, Lewis, and secretor genes with subsequent correspondence between the blood group antigens expressed on erythrocytes and on oral epithelial cells. Variation in expression of carbohydrates is also seen in relationship to terminal differentiation in that blood group antigens and their immediate precursor structures are sequentially expressed on cells during their pathway through the epithelium. Various organs and tissues differ in their expression of cell surface carbohydrates. In oral mucosa, a close relationship is seen between the type of tissue differentiation and expression of blood group antigen; keratinized, nonkeratinized, and junctional epithelium all show different patterns of carbohydrate expression.
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Murashima, Aki, Shinichi Miyagawa, Yukiko Ogino, et al. "Essential Roles of Androgen Signaling in Wolffian Duct Stabilization and Epididymal Cell Differentiation." Endocrinology 152, no. 4 (2011): 1640–51. http://dx.doi.org/10.1210/en.2010-1121.
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Abstract The epididymis is a male accessory organ and functions for sperm maturation and storage under the control of androgen. The development of the epididymis is also androgen dependent. The Wolffian duct (WD), anlagen of the epididymis, is formed in both male and female embryos; however, it is stabilized only in male embryos by testicular androgen. Androgen drives subsequent differentiation of the WD into the epididymis. Although the essential roles of androgen in WD masculinization and epididymal function have been established, little is known about cellular events regulated precisely by androgen signaling during these processes. It is also unclear whether androgen signaling, especially in the epithelia, has further function for epididymal epithelial cell differentiation. In this study we examined the cellular death and proliferation controlled by androgen signaling via the androgen receptor (AR) in WD stabilization. Analyses using AR knockout mice revealed that androgen signaling inhibits epithelial cell death in this process. Analysis of AP2α-Cre;ARflox/Y mice, in which AR function is deleted in the WD epithelium, revealed that epithelial AR is not required for the WD stabilization but is required for epithelial cell differentiation in the epididymis. Specifically, loss of epithelial AR significantly reduced expression of p63 that is essential for differentiation of basal cells in the epididymal epithelium. We also interrogated the possibility of regulation of the p63 gene (Trp63) by AR in vitro and found that p63 is a likely direct target of AR regulation.
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Liston, Adrian, Andrew G. Farr, Zhibin Chen, et al. "Lack of Foxp3 function and expression in the thymic epithelium." Journal of Experimental Medicine 204, no. 3 (2007): 475–80. http://dx.doi.org/10.1084/jem.20062465.
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Foxp3 is essential for the commitment of differentiating thymocytes to the regulatory CD4+ T (T reg) cell lineage. In humans and mice with a genetic Foxp3 deficiency, absence of this critical T reg cell population was suggested to be responsible for the severe autoimmune lesions. Recently, it has been proposed that in addition to T reg cells, Foxp3 is also expressed in thymic epithelial cells where it is involved in regulation of early thymocyte differentiation and is required to prevent autoimmunity. Here, we used genetic tools to demonstrate that the thymic epithelium does not express Foxp3. Furthermore, we formally showed that genetic abatement of Foxp3 in the hematopoietic compartment, i.e. in T cells, is both necessary and sufficient to induce the autoimmune lesions associated with Foxp3 loss. In contrast, deletion of a conditional Foxp3 allele in thymic epithelial cells did not result in detectable changes in thymocyte differentiation or pathology. Therefore, in mice the only known role for Foxp3 remains promotion of T reg cell differentiation within the T cell lineage, whereas there is no role for Foxp3 in thymic epithelial cells.
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Li, Feng, Jinxi He, Jun Wei, William C. Cho, and Xiaoming Liu. "Diversity of Epithelial Stem Cell Types in Adult Lung." Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/728307.
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Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays,in vitroand/orex vivomodels, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer.
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Jetten, A. M. "Growth and differentiation factors in tracheobronchial epithelium." American Journal of Physiology-Lung Cellular and Molecular Physiology 260, no. 6 (1991): L361—L373. http://dx.doi.org/10.1152/ajplung.1991.260.6.l361.
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The normal tracheobronchial epithelium is continuously renewing itself: cells are lost and replaced by the proliferation and differentiation of stem cells. The proliferation and differentiation of these cells have to be tightly controlled in order to maintain the normal structure of the epithelium. A variety of biological and biochemical processes are involved in controlling the proliferation and differentiation of the tracheobronchial epithelium. Since the trachea and bronchus are comprised of a heterogeneous cell population, interactions between the different cell types are of crucial importance not only in controlling the normal maintenance of this tissue but also in the regulation of repair processes following injury and morphogenesis during lung development. A variety of factors, including several polypeptide growth factors and cytokines, have been identified that regulate positively or negatively the growth and differentiation of tracheobronchial epithelial cells by autocrine or paracrine mechanisms. Retinoids are another group of regulatory factors that appear to play a crucial role in controlling cell proliferation and differentiation in the tracheobronchial epithelium. Recently, many advances have been made in understanding the action of these agents in these cells. Alterations in the balance between growth and differentiation regulatory factors appear to play an important role in several pathophysiological changes such as hyperplasia, fibrosis, and neoplasia.
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Turcatel, Gianluca, Katelyn Millette, Matthew Thornton, et al. "Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 2 (2017): L196—L207. http://dx.doi.org/10.1152/ajplung.00127.2016.
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The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9Δ/Δmutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B ( Sftpb), secretoglobulin, family 1A, member 1 ( Scgb1a1), and trefoil factor 1 ( Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-α and IFN-γ interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-β1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb ( Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 ( Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-α, IFN-γ, and TGF-β signaling pathways.
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Otto, Tobias, Sheyla V. Candido, Mary S. Pilarz, et al. "Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit." Proceedings of the National Academy of Sciences 114, no. 40 (2017): 10660–65. http://dx.doi.org/10.1073/pnas.1702914114.
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MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.
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Ikeda, Masakazu, Mitsuyoshi Imaizumi, Susumu Yoshie, et al. "Implantation of Induced Pluripotent Stem Cell–Derived Tracheal Epithelial Cells." Annals of Otology, Rhinology & Laryngology 126, no. 7 (2017): 517–24. http://dx.doi.org/10.1177/0003489417713504.
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Objectives: Compared with using autologous tissue, the use of artificial materials in the regeneration of tracheal defects is minimally invasive. However, this technique requires early epithelialization on the inner side of the artificial trachea. After differentiation from induced pluripotent stem cells (iPSCs), tracheal epithelial tissues may be used to produce artificial tracheas. Herein, we aimed to demonstrate that after differentiation from fluorescent protein-labeled iPSCs, tracheal epithelial tissues survived in nude rats with tracheal defects. Methods: Red fluorescent tdTomato protein was electroporated into mouse iPSCs to produce tdTomato-labeled iPSCs. Embryoid bodies derived from these iPSCs were then cultured in differentiation medium supplemented with growth factors, followed by culture on air-liquid interfaces for further differentiation into tracheal epithelium. The cells were implanted with artificial tracheas into nude rats with tracheal defects on day 26 of cultivation. On day 7 after implantation, the tracheas were exposed and examined histologically. Results: Tracheal epithelial tissue derived from tdTomato-labeled iPSCs survived in the tracheal defects. Moreover, immunochemical analyses showed that differentiated tissues had epithelial structures similar to those of proximal tracheal tissues. Conclusions: After differentiation from iPSCs, tracheal epithelial tissues survived in rat bodies, warranting the use of iPSCs for epithelial regeneration in tracheal defects.
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Horster, Michael F., Gerald S. Braun, and Stephan M. Huber. "Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation." Physiological Reviews 79, no. 4 (1999): 1157–91. http://dx.doi.org/10.1152/physrev.1999.79.4.1157.
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Embryonic metanephroi, differentiating into the adult kidney, have come to be a generally accepted model system for organogenesis. Nephrogenesis implies a highly controlled series of morphogenetic and differentiation events that starts with reciprocal inductive interactions between two different primordial tissues and leads, in one of two mainstream processes, to the formation of mesenchymal condensations and aggregates. These go through the intricate process of mesenchyme-to-epithelium transition by which epithelial cell polarization is initiated, and they continue to differentiate into the highly specialized epithelial cell populations of the nephron. Each step along the developmental metanephrogenic pathway is initiated and organized by signaling molecules that are locally secreted polypeptides encoded by different gene families and regulated by transcription factors. Nephrogenesis proceeds from the deep to the outer cortex, and it is directed by a second, entirely different developmental process, the ductal branching of the ureteric bud-derived collecting tubule. Both systems, the nephrogenic (mesenchymal) and the ductogenic (ureteric), undergo a repeat series of inductive signaling that serves to organize the architecture and differentiated cell functions in a cascade of developmental gene programs. The aim of this review is to present a coherent picture of principles and mechanisms in embryonic renal epithelia.
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Yao, Jiayi, Pierre J. Guihard, Xiuju Wu, et al. "Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation." Journal of Cell Biology 216, no. 10 (2017): 3369–85. http://dx.doi.org/10.1083/jcb.201612122.
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The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 α (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial–epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation.
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Nakajima, Tadaaki, Naoto Sakai, Miho Nogimura, and Yasuhiro Tomooka. "Developmental mechanisms regulating the formation of smooth muscle layers in the mouse uterus†." Biology of Reproduction 103, no. 4 (2020): 750–59. http://dx.doi.org/10.1093/biolre/ioaa104.
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Abstract Uterine smooth muscle cells differentiate from mesenchymal cells, and gap junctions connect the muscle cells in the myometrium. At the neonatal stage, a uterine smooth muscle layer is situated away from the epithelium when smooth muscle cells are grafted near the epithelium, suggesting that the epithelium plays an important role in differentiation, proliferation, and/or migration of smooth muscle cells. In this study, developmental mechanisms regulating the formation of the smooth muscle layers in the mouse uterus were analyzed using an in vitro culture model. Differentiation of smooth muscle cells occurs at a neonatal stage because ACTA2 gene expression was increased at the outer layer, and GJA1 was not expressed in cellular membranes of uterine smooth muscle cells by postnatal day 15. To analyze the effects of the epithelium on the differentiation of smooth muscle cells, a bulk uterine mesenchymal cell line was established from p53−/− mice at postnatal day 3 (P3US cells). Co-culture with Müllerian ductal epithelial cells (E1 cells) induced repulsive migration of ACTA2-positive cells among bulk P3US cells from E1 cells, but it had no effects on the migration of any of 100% ACTA2-positive or negative smooth muscle cell lines cloned from P3US cells. Thus, uterine epithelial cells indirectly affected the repulsive migration of smooth muscle cells via mesenchymal cells. Conditioned medium by E1 cells inhibited differentiation into smooth muscle cells of clonal cells established from P3US cells. Therefore, the uterine epithelium inhibits the differentiation of stem-like progenitor mesenchymal cells adjacent to the epithelium into smooth muscle cells.
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Harris, L. L., J. C. Talian, and P. S. Zelenka. "Contrasting patterns of c-myc and N-myc expression in proliferating, quiescent, and differentiating cells of the embryonic chicken lens." Development 115, no. 3 (1992): 813–20. http://dx.doi.org/10.1242/dev.115.3.813.
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The present study uses the polymerase chain reaction and in situ hybridization to examine c-myc and N-myc mRNA in the embryonic chicken lens at 6, 10, 14 and 19 days of development and compares the pattern of expression obtained with the developmental pattern of cell proliferation and differentiation. In the central epithelium, c-myc mRNA levels were proportional to the percentage of proliferating cells throughout development. N-myc mRNA expression in this region was relatively low and showed no correlation with cell proliferation. The ratio of N-myc to c-myc mRNA increased markedly with the onset of epithelial cell elongation and terminal fiber cell differentiation, although both c-myc and N-myc mRNAs continued to be expressed in postmitotic, elongating cells of the equatorial epithelium and in terminally differentiating lens fiber cells. Thus, increased expression of N-myc, a gene whose protein product may compete with c-myc protein for dimerization partners, accompanies the dissociation of c-myc expression and cell proliferation during terminal differentiation of lens fiber cells.
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Ta, B. M., G. T. Gallagher, R. Chakravarty, and R. H. Rice. "Keratinocyte transglutaminase in human skin and oral mucosa: cytoplasmic localization and uncoupling of differentiation markers." Journal of Cell Science 95, no. 4 (1990): 631–38. http://dx.doi.org/10.1242/jcs.95.4.631.
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Expression of keratinocyte transglutaminase, a specific differentiation marker, has been examined by immunogold-silver cytochemistry in human epidermis and oral epithelium, and in oral mucosal hyperplasia and neoplasia. Two major findings have been obtained. First, considerable immunoreactivity was evident not only at the plasma membrane (the site of cross-linked envelope formation) but also in the cytoplasm of spinous cells, suggesting a cytoplasmic function for this transglutaminase. Staining at the cell border was seen principally in the granular layer of orthokeratinized epithelium (epidermis, hard palate), the outer spinous cells of ortho- and parakeratinized epithelium and in the suprabasal cells showing squamous differentiation in benign and malignant neoplasms. By contrast, diffuse cytoplasmic staining was observed in the upper spinous layer of the normal epithelium and benign lesions. The cytoplasmic immunoreactivity, which extended nearly to the basal layer in hyperkeratosis of the oral mucosa, was evident in two of three verrucous carcinomas examined. In keeping with their undifferentiated character, invasive nests of squamous cell carcinoma and basaloid epithelium in benign and neoplastic lesions were immunonegative for transglutaminase. The second major finding was that lesions of severe oral epithelial dysplasia, immunonegative for transglutaminase, were capable of expressing involucrin immunoreactivity, indicating an uncoupling of keratinocyte programming. These results suggest that immunogold-silver staining for transglutaminase may be useful in evaluating the degree of differentiation in benign and malignant oral epithelial proliferation.
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JEZERNIK, K., and M. STERLE. "The mouse urinary bladder epithelium differentiation." Cell Biology International Reports 14 (September 1990): 170. http://dx.doi.org/10.1016/0309-1651(90)90782-t.
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Miyoshi, Keiko, Jonathan M. Shillingford, Gilbert H. Smith, et al. "Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium." Journal of Cell Biology 155, no. 4 (2001): 531–42. http://dx.doi.org/10.1083/jcb.200107065.
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Functional development of mammary epithelium during pregnancy depends on prolactin signaling. However, the underlying molecular and cellular events are not fully understood. We examined the specific contributions of the prolactin receptor (PrlR) and the signal transducers and activators of transcription 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrlR- and Stat5-null mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5-null mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrlR-null epithelium formed alveoli-like structures with small open lumina. Electron microscopy revealed undifferentiated features of organelles and a perturbation of cell–cell contacts in PrlR- and Stat5-null epithelia. Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5-null epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5-null mice. These data demonstrate that signaling via the PrlR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.
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Bhat, Pangala V., Thomas Bader, Paul Nettesheim, and Anton M. Jetten. "Differentiation-dependent regulation of retinal dehydrogenase gene expression in the trachea." Biochemistry and Cell Biology 76, no. 1 (1998): 59–62. http://dx.doi.org/10.1139/o98-005.
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Retinoic acid (RA), a metabolite of vitamin A, is known to be a key signaling molecule in regulating epithelial cell differentiation. We recently characterized and cloned a retinal dehydrogenase (RALDH) that catalyzes the oxidation of retinal to RA. In this study, we investigated the effects of retinoids on the level of RALDH mRNA and protein as well as RALDH activity in the trachea and cultured tracheal epithelial cells. Vitamin A deficiency induced squamous metaplasia in the tracheal epithelium and down-regulated RALDH expression. Supplementation of retinol and retinoic acid to vitamin A deficient rats restored the normal mucociliary epithelium and up-regulated the RALDH expression. In rat epithelial cells cultured in vitro, RAinhibited squamous differentiation and promoted mucociliary differentiation. Squamous differentiated cultures (RA-) expressed very low levels of RALDH mRNA, whereas mucociliary differentiated cultures (RA+) expressed high levels of RALDH mRNA. Retinal and retinol were poor inducers of mucociliary differentiation as well as RALDH expression. The RALDH expression paralleled the expression of the mucin-1 gene in mucociliary cultures. These results suggest that the expression of RALDH is dependent on the differentiation state of the airway epithelium.Key words: retinoic acid, retinal dehydrogenase, gene expression, tracheal epithelium.
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Trautman, M. S., J. Kimelman, and M. Bernfield. "Developmental expression of syndecan, an integral membrane proteoglycan, correlates with cell differentiation." Development 111, no. 1 (1991): 213–20. http://dx.doi.org/10.1242/dev.111.1.213.
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Syndecan is an integral membrane proteoglycan that behaves as a matrix receptor by binding cells to interstitial matrix and associating intracellularly with the actin cytoskeleton. Using immunohistology, we have now localized this proteoglycan during the morphogenesis of various derivatives of the surface ectoderm in mouse embryos. Syndecan is expressed on ectodermal epithelia, but is selectively lost from the cells that differentiate into the localized placodes that initiate lens, nasal, otic and vibrissal development. The loss is transient on presumptive ear, nasal and vibrissal epithelia; the derivatives of the differentiating ectodermal cells that have lost syndecan subsequently re-express syndecan. In contrast, syndecan is initially absent from the mesenchyme underlying the surface ectoderm, and is transiently expressed when the surface ectoderm loses syndecan. These results demonstrate that expression of syndecan is developmentally regulated in a distinct spatiotemporal pattern. On epithelia, syndecan is lost at a time and, location that correlates with epithelial cell differentiation and, on mesenchyme, syndecan is acquired when the cells aggregate in proximity to the epithelium. This pattern of change with morphogenetic events is unique and not duplicated by other matrix molecules or adhesion receptors.
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Sayols, Sergi, Jakub Klassek, Clara Werner, et al. "Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors." Development 147, no. 18 (2020): dev188839. http://dx.doi.org/10.1242/dev.188839.
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ABSTRACTThe identity of embryonic gastric epithelial progenitors is unknown. We used single-cell RNA-sequencing, genetic lineage tracing and organoid assays to assess whether Axin2- and Lgr5-expressing cells are gastric progenitors in the developing mouse stomach. We show that Axin2+ cells represent a transient population of embryonic epithelial cells in the forestomach. Lgr5+ cells generate both glandular corpus and squamous forestomach organoids ex vivo. Only Lgr5+ progenitors give rise to zymogenic cells in culture. Modulating the activity of the WNT, BMP and Notch pathways in vivo and ex vivo, we found that WNTs are essential for the maintenance of Lgr5+ epithelial cells. Notch prevents differentiation of the embryonic epithelial cells along all secretory lineages and hence ensures their maintenance. Whereas WNTs promote differentiation of the embryonic progenitors along the zymogenic cell lineage, BMPs enhance their differentiation along the parietal lineage. In contrast, WNTs and BMPs are required to suppress differentiation of embryonic gastric epithelium along the pit cell lineage. Thus, coordinated action of the WNT, BMP and Notch pathways controls cell fate determination in the embryonic gastric epithelium.
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Naylor, Matthew J., Na Li, Julia Cheung та ін. "Ablation of β1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation". Journal of Cell Biology 171, № 4 (2005): 717–28. http://dx.doi.org/10.1083/jcb.200503144.
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Integrin-mediated adhesion regulates the development and function of a range of tissues; however, little is known about its role in glandular epithelium. To assess the contribution of β1 integrin, we conditionally deleted its gene in luminal epithelia during different stages of mouse mammary gland development and in cultured primary mammary epithelia. Loss of β1 integrin in vivo resulted in impaired alveologenesis and lactation. Cultured β1 integrin–null cells displayed abnormal focal adhesion function and signal transduction and could not form or maintain polarized acini. In vivo, epithelial cells became detached from the extracellular matrix but remained associated with each other and did not undergo overt apoptosis. β1 integrin–null mammary epithelial cells did not differentiate in response to prolactin stimulation because of defective Stat5 activation. In mice where β1 integrin was deleted after the initiation of differentiation, fewer defects in alveolar morphology occurred, yet major deficiencies were also observed in milk protein and milk fat production and Stat5 activation, indicating a permissive role for β1 integrins in prolactin signaling. This study demonstrates that β1 integrin is critical for the alveolar morphogenesis of a glandular epithelium and for maintenance of its differentiated function. Moreover, it provides genetic evidence for the cooperation between integrin and cytokine signaling pathways.
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Yeh, Yi-Chun, Hsi-Hui Lin та Ming-Jer Tang. "A tale of two collagen receptors, integrin β1 and discoidin domain receptor 1, in epithelial cell differentiation". American Journal of Physiology-Cell Physiology 303, № 12 (2012): C1207—C1217. http://dx.doi.org/10.1152/ajpcell.00253.2012.
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As increase in collagen deposition is no longer taken as simply a consequence but, rather, an inducer of disease progression; therefore, the understanding of collagen signal transduction is fundamentally important. Cells contain at least two types of collagen receptors: integrins and discoidin domain receptors (DDRs). The integrin heterodimers α1β1, α2β1, α10β1, and α11β1 are recognized as the non-tyrosine kinase collagen receptors. DDR1 and 2, the tyrosine kinase receptors of collagen, are specifically expressed in epithelium and mesenchyme, respectively. While integrin β1 and DDR1 are both required for cell adhesion on collagen, their roles in epithelial cell differentiation during development and disease progression seem to counteract each other, with integrin β1 favoring epithelium mesenchyme transition (EMT) and DDR1 inducing epithelial cell differentiation. The in vitro evidence shows that the integrin β1 and DDR1 exert opposing actions in regulation of membrane stability of E-cadherin, which itself is a critical regulator of epithelial cell differentiation. Here, we review the functional roles of integrin β1 and DDR1 in regulation of epithelial cell differentiation during development and disease progression, and explore the underlining mechanisms regarding to the regulation of membrane stability of E-cadherin.
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Hyenne, Vincent, Juergen C. Harf, Martin Latz, Bernard Maro, Uwe Wolfrum, and Marie-Christine Simmler. "Vezatin, a ubiquitous protein of adherens cell–cell junctions, is exclusively expressed in germ cells in mouse testis." Reproduction 133, no. 3 (2007): 563–74. http://dx.doi.org/10.1530/rep-06-0271.
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In the male reproductive organs of mammals, the formation of spermatozoa takes place during two successive phases: differentiation (in the testis) and maturation (in the epididymis). The first phase, spermiogenesis, relies on a unique adherens junction, the apical ectoplasmic specialization linking the epithelial Sertoli cells to immature differentiating spermatids. Vezatin is a transmembrane protein associated with adherens junctions and the actin cytoskeleton in most epithelial cells. We report here the expression profile of vezatin during spermatogenesis. Vezatin is exclusively expressed in haploid germ cells. Immunocytochemical and ultrastructural analyses showed that vezatin intimately coincides, temporally and spatially, with acrosome formation. While vezatin is a transmembrane protein associated with adherens junctions in many epithelial cells, it is not seen at the ectoplasmic specializations, neither at the basal nor at the apical sites, in the seminiferous epithelium. In particular, vezatin does not colocalize with espin and myosin VIIa, two molecular markers of the ectoplasmic specialization. In differentiating spermatids, ultrastructural data indicate that vezatin localizes in the acrosome. In epididymal sperm, vezatin localizes also to the outer acrosomal membrane. Considering its developmental and molecular characteristics, vezatin may be involved in the assembly/stability of this spermatic membrane.
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Cirulli, V., L. Crisa, G. M. Beattie, et al. "KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development." Journal of Cell Biology 140, no. 6 (1998): 1519–34. http://dx.doi.org/10.1083/jcb.140.6.1519.
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Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell–cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny.
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Xiong, Y., Y. Fang, Y. Qian, et al. "Wnt Production in Dental Epithelium Is Crucial for Tooth Differentiation." Journal of Dental Research 98, no. 5 (2019): 580–88. http://dx.doi.org/10.1177/0022034519835194.
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The Wnt ligands display varied spatiotemporal expression in the epithelium and mesenchyme in the developing tooth. Thus far, the actions of these differentially expressed Wnt ligands on tooth development are not clear. Shh expression specifies the odontogenic epithelium during initiation and is consistently restricted to the dental epithelium during tooth development. In this study, we inactivate Wntless ( Wls), the key regulator for Wnt trafficking, by Shh-Cre to investigate how the Wnt ligands produced in the dental epithelium lineage act on tooth development. We find that conditional knockout of Wls by Shh-Cre leads to defective ameloblast and odontoblast differentiation. WlsShh-Cre teeth display reduced canonical Wnt signaling activity in the inner enamel epithelium and the underlying mesenchyme at the early bell stage, as exhibited by target gene expression and BAT-gal staining. The expression of Wnt5a and Wnt10b is not changed in WlsShh-Cre teeth. By contrast, Wnt10a expression is significantly increased in response to epithelial Wls deficiency. In addition, the expression of Hedgehog signaling pathway components Shh, Gli1, and Patched1 was greatly decreased in WlsShh-Cre teeth. Epithelial Wls loss of function in Shh lineage also leads to aberrant cell proliferation in dental epithelium and mesenchyme at embryonic day 16.5; however, the cell apoptosis is unaffected. Moreover, we find that Decorin and Col1a1, the key markers for odontoblast differentiation that are downregulated in WlsShh-Cre teeth, act as direct downstream targets of the canonical Wnt signaling pathway by chromatin immunoprecipitation analysis. Additionally, Decorin and Col1a1 expression can be increased by lithium chloride (LiCl) treatment in the in vitro tooth explants. Taken together, our results suggest that the spatial expression of Wnt ligands within the dental epithelial lineage regulates the differentiation of tooth structures in later stages.
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Kim, Hyun-Taek, Wenguang Yin, Yuko Nakamichi, et al. "WNT/RYK signaling restricts goblet cell differentiation during lung development and repair." Proceedings of the National Academy of Sciences 116, no. 51 (2019): 25697–706. http://dx.doi.org/10.1073/pnas.1911071116.
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Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in anN-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development;Rykmutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specificRykdeletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specificRykdeletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.
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Castro-Munozledo, F. "Development of a spontaneous permanent cell line of rabbit corneal epithelial cells that undergoes sequential stages of differentiation in cell culture." Journal of Cell Science 107, no. 8 (1994): 2343–51. http://dx.doi.org/10.1242/jcs.107.8.2343.
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Established epithelial cell lines that retain their differentiation potential and growth regulatory characteristics can provide valuable tools for studying gene regulation, extracellular matrix synthesis or growth factor response. They are also useful for drug development and toxicity testing. Experiments were therefore carried out to optimize culture conditions for the long-term, serial transfer of corneal epithelial cells in the presence of 3T3 feeder layers; and to establish a permanent cell line. In such experiments, rabbit corneal epithelial cells were seeded at low inoculation densities, and transferred every 5 days. After 80 population doublings, an epithelial cell line, RCE1, emerged. The cell line is heteroploid, with an average population doubling time of 15.5 hours (vs 18 hours for primary cultures). When RCE1 cells reached confluence, they stratified to form a three- to five-layered epithelium and expressed the differentiation-related keratin pair K3/K12 as shown by immunoblot and immunostaining. Biosynthetic labeling of proliferating, confluent and stratified cultures further showed that RCE1 cells expressed keratin pairs K5/K14, K6/K16 and K3/K12, thus mimicking faithfully the stage-dependent differentiation of primary cultures of rabbit corneal keratinocytes. The results demonstrated that RCE1 cells provide a useful model for studying corneal cell growth and differentiation.
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Basbaum, C., and B. Jany. "Plasticity in the airway epithelium." American Journal of Physiology-Lung Cellular and Molecular Physiology 259, no. 2 (1990): L38—L46. http://dx.doi.org/10.1152/ajplung.1990.259.2.l38.
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Normal cell turnover as well as the response to injury require cell proliferation and differentiation. The airway epithelium maintains these processes throughout adult life. Controlled homeostatically, cell proliferation and differentiation usually restore, as an end point, the pseudostratified architecture of the normal mucociliary epithelium. After injury, however, cell proliferation and differentiation sometimes establish, as an end point, regions of metaplastic cells. In this brief review, we have tried to summarize research findings that 1) describe the development of metaplastic lesions in morphological terms, 2) identify cells the proliferation of which forms the basis of these lesions, and 3) identify molecular changes within these cells that control development of the metaplastic phenotype.
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Vidalain, Pierre-Olivier, David Laine, Yona Zaffran, et al. "Interferons Mediate Terminal Differentiation of Human Cortical Thymic Epithelial Cells." Journal of Virology 76, no. 13 (2002): 6415–24. http://dx.doi.org/10.1128/jvi.76.13.6415-6424.2002.
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ABSTRACT In the thymus, epithelial cells comprise a heterogeneous population required for the generation of functional T lymphocytes, suggesting that thymic epithelium disruption by viruses may compromise T-cell lymphopoiesis in this organ. In a previous report, we demonstrated that in vitro, measles virus induced differentiation of cortical thymic epithelial cells as characterized by (i) cell growth arrest, (ii) morphological and phenotypic changes, and (iii) apoptotis as a final step of this process. In the present report, we have analyzed the mechanisms involved. First, measles virus-induced differentiation of thymic epithelial cells is shown to be strictly dependent on beta interferon (IFN-β) secretion. In addition, transfection with double-stranded RNA, a common intermediate of replication for a broad spectrum of viruses, is reported to similarly mediate thymic epithelial cell differentiation through IFN-β induction. Finally, we demonstrated that recombinant IFN-α, IFN-β, or IFN-γ was sufficient to induce differentiation and apoptosis of uninfected thymic epithelial cells. These observations suggested that interferon secretion by either infected cells or activated leukocytes, such as plasmacytoid dendritic cells or lymphocytes, may induce thymic epithelium disruption in a pathological context. Thus, we have identified a new mechanism that may contribute to thymic atrophy and altered T-cell lymphopoiesis associated with many infections.
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Jenkinson, William E., Eric J. Jenkinson, and Graham Anderson. "Differential Requirement for Mesenchyme in the Proliferation and Maturation of Thymic Epithelial Progenitors." Journal of Experimental Medicine 198, no. 2 (2003): 325–32. http://dx.doi.org/10.1084/jem.20022135.
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Formation of a mature thymic epithelial microenvironment is an essential prerequisite for the generation of a functionally competent T cell pool. It is likely that recently identified thymic epithelial precursors undergo phases of proliferation and differentiation to generate mature cortical and medullary thymic microenvironments. The mechanisms regulating development of immature thymic epithelial cells are unknown. Here we provide evidence that expansion of embryonic thymic epithelium is regulated by the continued presence of mesenchyme. In particular, mesenchymal cells are shown to mediate thymic epithelial cell proliferation through their provision of fibroblast growth factors 7 and 10. In contrast, differentiation of immature thymic epithelial cells, including acquisition of markers of mature cortical and medullary epithelium, occurs in the absence of ongoing mesenchymal support. Collectively, our data define a role for mesenchymal cells in thymus development, and indicate distinct mechanisms regulate proliferation and differentiation of immature thymic epithelial cells. In addition, our findings may aid in studies aimed at developing strategies to enhance thymus reconstitution and functioning in clinical certain contexts where thymic epithelial cell function is perturbed.
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Quaroni, A. "Development of fetal rat intestine in organ and monolayer culture." Journal of Cell Biology 100, no. 5 (1985): 1611–22. http://dx.doi.org/10.1083/jcb.100.5.1611.
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Maturation and differentiation of intestinal epithelial cells was demonstrated in segments of fetal rat small intestine, maintained for more than a month in suspension organ culture, by ultrastructural, biochemical, and immunological criteria. Over a 5-7 d period, fragments of fetal intestine evolved into globular structures covered with a single columnar epithelium ultrastructurally similar to suckling villus cells. Loose mesenchymal cells, cellular debris, and collagen were present inside the structures. After 6 d in culture, goblet cells, not present in the fetal intestine at day 18, were numerous and well developed. Intestinal endocrine cells were also observed. Immunofluorescence studies employing monoclonal antibodies specific for villus and crypt cells in vivo, and various enzyme assays, have demonstrated a level of differentiation and maturation of the cultured epithelial cells similar but not identical to that of suckling intestinal mucosa in vivo. Crypts and crypt cell markers were not observed in the the cultures. Addition of glucocorticoids to the culture medium resulted in the induction of sucrase-isomaltase but failed to promote most of the functional changes characteristic of the intestinal epithelium at weaning in vivo. Epithelial cells were identified in explants derived from the organ cultures by their specific expression of intestinal cytokeratin. Differentiation-specific markers, present in the epithelial cells in primary cultures, were lost upon selection and subculturing of pure epithelial cell populations. These results suggest a requirement for mesenchymal and/or extracellular matrix components in the maintenance of the differentiated state of the epithelial cells. The fetal intestinal organ cultures described here present significant advantages over traditional organ and monolayer culture techniques for the study of the cellular and molecular interactions involved in the development and differentiation of the intestinal epithelium.
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Shih, J., and R. Keller. "The epithelium of the dorsal marginal zone of Xenopus has organizer properties." Development 116, no. 4 (1992): 887–99. http://dx.doi.org/10.1242/dev.116.4.887.
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We have investigated the properties of the epithelial layer of the dorsal marginal zone (DMZ) of the Xenopus laevis early gastrula and found that it has inductive properties similar to those of the entire Spemann organizer. When grafts of the epithelial layer of the DMZ of early gastrulae labelled with fluorescein dextran were transplanted to the ventral sides of unlabelled host embryos, they induced secondary axes composed of notochord, somites and posterior neural tube. The organizer epithelium rescued embryos ventralized by UV irradiation, inducing notochord, somites and posterior neural tube in these embryos, while over 90% of ventralized controls showed no such structures. Combinations of organizer epithelium and ventral marginal zone (VMZ) in explants of the early gastrula resulted in convergence, extension and differentiation of dorsal mesodermal tissues, whereas similar recombinants of nonorganizer epithelium and the VMZ did none of these things. In all cases, the axial structures forming in response to epithelial grafts were composed of labelled graft and unlabelled host cells, indicating an induction by the organizer epithelium of dorsal, axial morphogenesis and tissue differentiation among mesodermal cells that otherwise showed non-axial development. Serial sectioning and scanning electron microscopy of control grafts shows that the epithelial organizer effect occurs in the absence of contaminating deep cells adhering to the epithelial grafts. However, labelled organizer epithelium grafted to the superficial cell layer contributed cells to deep mesodermal tissues, and organizer epithelium developed into mesodermal tissues when deliberately grafted into the deep region. This shows that these prospective endodermal epithelial cells are able to contribute to mesodermal, mesenchymal tissues when they move or are moved into the deep environment. These results suggest that in normal development, the endodermal epithelium may influence some aspects of the cell motility underlying the mediolateral intercalation (see Shih, J. and Keller, R. (1992) Development 116, 901–914), as well as the tissue differentiation of mesodermal cells. These results have implications for the analysis of mesoderm induction and for analysis of variations in the differentiation and morphogenetic function of the marginal zone in different species of amphibians.
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Bastide, Pauline, Charbel Darido, Julie Pannequin, et al. "Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium." Journal of Cell Biology 178, no. 4 (2007): 635–48. http://dx.doi.org/10.1083/jcb.200704152.
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The HMG-box transcription factor Sox9 is expressed in the intestinal epithelium, specifically, in stem/progenitor cells and in Paneth cells. Sox9 expression requires an active β-catenin–Tcf complex, the transcriptional effector of the Wnt pathway. This pathway is critical for numerous aspects of the intestinal epithelium physiopathology, but processes that specify the cell response to such multipotential signals still remain to be identified. We inactivated the Sox9 gene in the intestinal epithelium to analyze its physiological function. Sox9 inactivation affected differentiation throughout the intestinal epithelium, with a disappearance of Paneth cells and a decrease of the goblet cell lineage. Additionally, the morphology of the colon epithelium was severely altered. We detected general hyperplasia and local crypt dysplasia in the intestine, and Wnt pathway target genes were up-regulated. These results highlight the central position of Sox9 as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis.
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Gang, Du-Gyeong, Cheul-Hyeon Sim, Tae-Je Lee, Joo-Yeon Kong, and Il-Hwa Hong. "Sebaceous cell differentiation in a canine oral papilloma." Journal of Veterinary Diagnostic Investigation 30, no. 4 (2018): 569–71. http://dx.doi.org/10.1177/1040638718779102.
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Papillomas caused by viral infection are well-known tumors in animals. Microscopic features typically include neoplastic epithelium with hyperkeratosis and koilocytes. An 8-y-old castrated male Shih Tzu dog was presented with a small exophytic mass on the external upper lip. The mass was diagnosed as a viral papilloma based on microscopic and immunohistochemical examination. Sebaceous cell differentiation was found in the neoplastic epithelium of the tumor, which is a rare finding in humans or animals.
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Zhu, Maobi, Tomohiko Iwano, and Sen Takeda. "Fallopian Tube Basal Stem Cells Reproducing the Epithelial Sheets In Vitro—Stem Cell of Fallopian Epithelium." Biomolecules 10, no. 9 (2020): 1270. http://dx.doi.org/10.3390/biom10091270.
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The fallopian tube (FT) is an important reproductive organ in females. The luminal epithelium of the FT is composed of highly polarized secretory and ciliated cells. Recently, accumulating lines of evidence have suggested that the origin of high-grade serous ovarian carcinoma (HGSC) is fallopian tube epithelial cells (FTECs). Due to the lack of a high-fidelity model for FTECs in vitro, homeostasis, differentiation, as well as the transformation of FTECs are still enigmatic. In this study, we optimized the culture condition for the stable expansion of basal stem cells, as well as inducing differentiation of basal cells into polarized secretory and ciliated cells in the air–liquid interface (ALI) condition suitable for long-term culture. This storable culture method of FTECs provides a versatile platform for studying differentiation mechanisms, intercellular communication, and transformation to HGSC, as well as the physiological function of the FT in vitro.
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Shannon, J. M., S. A. Gebb, and L. D. Nielsen. "Induction of alveolar type II cell differentiation in embryonic tracheal epithelium in mesenchyme-free culture." Development 126, no. 8 (1999): 1675–88. http://dx.doi.org/10.1242/dev.126.8.1675.
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We have previously shown that fetal lung mesenchyme can reprogram embryonic rat tracheal epithelium to express a distal lung phenotype. We have also demonstrated that embryonic rat lung epithelium can be induced to proliferate and differentiate in the absence of lung mesenchyme. In the present study we used a complex growth medium to induce proliferation and distal lung epithelial differentiation in embryonic tracheal epithelium. Day-13 embryonic rat tracheal epithelium was separated from its mesenchyme, enrobed in growth factor-reduced Matrigel, and cultured for up to 7 days in medium containing charcoal-stripped serum, insulin, epidermal growth factor, hepatocyte growth factor, cholera toxin, fibroblast growth factor 1 (FGF1), and keratinocyte growth factor (FGF7). The tracheal epithelial cells proliferated extensively in this medium, forming lobulated structures within the extracellular matrix. Many of the cells differentiated to express a type II epithelial cell phenotype, as evidenced by expression of SP-C and osmiophilic lamellar bodies. Deletion studies showed that serum, insulin, cholera toxin, and FGF7 were necessary for maximum growth. While no single deletion abrogated expression of SP-C, deleting both FGF7 and FGF1 inhibited growth and prevented SP-C expression. FGF7 or FGF1 as single additions to the medium, however, were unable to induce SP-C expression, which required the additional presence of serum or cholera toxin. FGF10, which binds the same receptor as FGF7, did not support transdifferentiation when used in place of FGF7. These data indicate that FGF7 is necessary, but not sufficient by itself, to induce the distal rat lung epithelial phenotype, and that FGF7 and FGF10 play distinct roles in lung development.
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Soares, Eduardo, Quan Xu, Qingqing Li, et al. "Single-cell RNA-seq identifies a reversible mesodermal activation in abnormally specified epithelia of p63 EEC syndrome." Proceedings of the National Academy of Sciences 116, no. 35 (2019): 17361–70. http://dx.doi.org/10.1073/pnas.1908180116.
Full textAbstract:
Mutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed stepwise cell fate transitions during epidermal commitment: Specification from multipotent simple epithelium to basal stratified epithelia and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by p63 mutations occurred during the specification switch from the simple epithelium to the basal-stratified epithelial fate. Single-cell transcriptome and pseudotime analyses of cell states identified mesodermal activation that was associated with the deviated commitment route of EEC iPSCs. Integrated analyses of differentially regulated genes and p63-dependent dynamic genomic enhancers during epidermal commitment suggest that p63 directly controls epidermal gene activation at the specification switch and has an indirect effect on mesodermal gene repression. Importantly, inhibitors of mesodermal induction enhanced epidermal commitment of EEC iPSCs. Our findings demonstrate that p63 is required for specification of stratified epithelia, and that epidermal commitment defects caused by p63 mutations can be reversed by repressing mesodermal induction. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.
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Zhang, Haihan, Dongfeng Li, Lingbin Liu, et al. "Cellular Composition and Differentiation Signaling in Chicken Small Intestinal Epithelium." Animals 9, no. 11 (2019): 870. http://dx.doi.org/10.3390/ani9110870.
Full textAbstract:
The small intestine plays an important role for animals to digest and absorb nutrients. The epithelial lining of the intestine develops from the embryonic endoderm of the embryo. The mature intestinal epithelium is composed of different types of functional epithelial cells that are derived from stem cells, which are located in the crypts. Chickens have been widely used as an animal model for researching vertebrate embryonic development. However, little is known about the molecular basis of development and differentiation within the chicken small intestinal epithelium. This review introduces processes of development and growth in the chicken gut, and compares the cellular characteristics and signaling pathways between chicken and mammals, including Notch and Wnt signaling that control the differentiation in the small intestinal epithelium. There is evidence that the chicken intestinal epithelium has a distinct cellular architecture and proliferation zone compared to mammals. The establishment of an in vitro cell culture model for chickens will provide a novel tool to explore molecular regulation of the chicken intestinal development and differentiation.
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Hasegawa, Daisuke, Veronica Calvo, Alvaro Avivar-Valderas, et al. "Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development." Molecular and Cellular Biology 35, no. 9 (2015): 1543–56. http://dx.doi.org/10.1128/mcb.00136-15.
Full textAbstract:
Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development.
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Oshima, Tadayuki, Karin Gedda, Junichi Koseki, et al. "Establishment of esophageal-like non-keratinized stratified epithelium using normal human bronchial epithelial cells." American Journal of Physiology-Cell Physiology 300, no. 6 (2011): C1422—C1429. http://dx.doi.org/10.1152/ajpcell.00376.2010.
Full textAbstract:
Current experimental models of esophageal epithelium in vitro suffer from either poor differentiation or complicated culture systems. We have established a model to study stratified squamous epithelium in vitro, which is very similar to esophageal epithelium in vivo. A stratified squamous multilayer epithelium was formed by seeding primary normal human bronchial epithelial (NHBE) cells onto collagen- and fibronectin-coated trans-well inserts and then cultivating the cells under air-liquid interface (ALI) conditions in the presence of growth factors and low levels of all-trans-retinoic acid. Trans-epithelial electrical resistance (TEER) measurements revealed the presence of a tight barrier, previously only achievable with esophageal biopsies mounted in Ussing chambers. Molecular markers for desmosomes, cornified envelope, tight junctions, and mature esophageal epithelium were upregulated in the differentiating culture in parallel with functional properties, such as decreased permeability and acid resistance and restoration. Acid exposure resulted in a decrease in TEER, but following 1-h recovery the TEER values were fully restored. Treatment with all-trans-retinoic acid decreased TEER and inhibited the recovery after acid challenge. PPAR-delta agonist treatment increased TEER, and this temporary increase in TEER was consistent with an increase in involucrin mRNA. Global gene expression analysis showed that ALI-differentiated NHBE cells had expression profiles more similar to epithelial biopsies from the esophageal tissue of healthy volunteers than to any other cell line. With respect to morphology, molecular markers, barrier properties, and acid resistance, this model presents a new way to investigate barrier properties and the possible effects of different agents on human esophagus-like epithelium.
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Amatngalim, Gimano D., Jasmijn A. Schrumpf, Fernanda Dishchekenian, et al. "Aberrant epithelial differentiation by cigarette smoke dysregulates respiratory host defence." European Respiratory Journal 51, no. 4 (2018): 1701009. http://dx.doi.org/10.1183/13993003.01009-2017.
Full textAbstract:
It is currently unknown how cigarette smoke-induced airway remodelling affects highly expressed respiratory epithelial defence proteins and thereby mucosal host defence.Localisation of a selected set of highly expressed respiratory epithelial host defence proteins was assessed in well-differentiated primary bronchial epithelial cell (PBEC) cultures. Next, PBEC were cultured at the air–liquid interface, and during differentiation for 2–3 weeks exposed daily to whole cigarette smoke. Gene expression, protein levels and epithelial cell markers were subsequently assessed. In addition, functional activities and persistence of the cigarette smoke-induced effects upon cessation were determined.Expression of the polymeric immunoglobulin receptor, secretory leukocyte protease inhibitor and long and short PLUNC (palate, lung and nasal epithelium clone protein) was restricted to luminal cells and exposure of differentiating PBECs to cigarette smoke resulted in a selective reduction of the expression of these luminal cell-restricted respiratory host defence proteins compared to controls. This reduced expression was a consequence of cigarette smoke-impaired end-stage differentiation of epithelial cells, and accompanied by a significant decreased transepithelial transport of IgA and bacterial killing.These findings shed new light on the importance of airway epithelial cell differentiation in respiratory host defence and could provide an additional explanation for the increased susceptibility of smokers and patients with chronic obstructive pulmonary disease to respiratory infections.