Journal articles: 'Definitive endoderm'

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Kaitsuka, Taku, Kohei Kobayashi, Wakako Otsuka, et al. "Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling." American Journal of Physiology-Cell Physiology 312, no. 5 (2017): C573—C582. http://dx.doi.org/10.1152/ajpcell.00071.2016.

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Artificially generated pancreatic β-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic β-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm. At an early stage of differentiation, EPO treatment significantly increased Sox17 gene expression, as a marker of the definitive endoderm. Contrary to the canonical function of EPO, it did not affect the levels of phosphorylated JAK2 and STAT5, but stimulated the phosphorylation of ERK1/2 and Akt. The MEK inhibitor U0126 significantly inhibited EPO-induced Sox17 expression. The differentiation of ESCs into definitive endoderm is an important step for the differentiation into pancreatic and other endodermal lineages. This study suggests a possible role of EPO in embryonic endodermal development and a new agent for directing the differentiation into endodermal lineages like pancreatic β-cells.

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Kanai-Azuma, Masami, Yoshiakira Kanai, Jacqueline M. Gad, et al. "Depletion of definitive gut endoderm in Sox17-null mutant mice." Development 129, no. 10 (2002): 2367–79. http://dx.doi.org/10.1242/dev.129.10.2367.

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In the mouse, the definitive endoderm is derived from the epiblast during gastrulation, and, at the early organogenesis stage, forms the primitive gut tube, which gives rise to the digestive tract, liver, pancreas and associated visceral organs. The transcription factors, Sox17 (a Sry-related HMG box factor) and its upstream factors, Mixer (homeobox factor) and Casanova (a novel Sox factor), have been shown to function as endoderm determinants in Xenopus and zebrafish, respectively. However, whether the mammalian orthologues of these genes are also involved with endoderm formation is not known. We show that Sox17–/– mutant embryos are deficient of gut endoderm. The earliest recognisable defect is the reduced occupancy by the definitive endoderm in the posterior and lateral region of the prospective mid- and hindgut of the headfold-stage embryo. The prospective foregut develops properly until the late neural plate stage. Thereafter, elevated levels of apoptosis lead to a reduction in the population of the definitive endoderm in the foregut. In addition, the mid- and hindgut tissues fail to expand. These are accompanied by the replacement of the definitive endoderm in the lateral region of the entire length of the embryonic gut by cells that resemble the visceral endoderm. In the chimeras, although Sox17-null ES cells can contribute unrestrictedly to ectodermal and mesodermal tissues, few of them could colonise the foregut endoderm and they are completely excluded from the mid- and hindgut endoderm. Our findings indicate an important role of Sox17 in endoderm development in the mouse, highlighting the idea that the molecular mechanism for endoderm formation is likely to be conserved among vertebrates.

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Semb, Henrik. "Definitive endoderm from embryonic stem cells." Regenerative Medicine 1, no. 4 (2006): 489–92. http://dx.doi.org/10.2217/17460751.1.4.489.

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Vroegindeweij, Erik, Wilhelmus J. Rombouts, Joanna A. Ropela, Shin-Ichi Nishikawa, Tom Cupedo, and Jan J. Cornelissen. "Towards Regenerative Therapy for Thymic Insufficiency after Hematopoietic Stem Cell Transplantation: Generation of MTS24 Positive Definitive Endoderm from Murine Embryonic Stem Cells." Blood 110, no. 11 (2007): 2241. http://dx.doi.org/10.1182/blood.v110.11.2241.2241.

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Abstract Following hematopoietic stem cell transplantation (HSCT), longterm T-cell reconstitution should be established by thymus-dependent de-novo generation of naïve T-cells (thymopoiesis), which is especially important for generating a naïve T-cell pool with a broad T-cell receptor (TCR) repertoire. However, while erythroid and myeloid hematopoietic cell lineages recover rapidly following HSCT, T-cell development may severely lag behind due to thymic insufficiency. Recent studies in fetal mice have identified common thymic epithelial progenitor cells (TEPC) that were capable to re-establish a thymus in-vivo upon transplantation into a-thymic nude mice. These TEPC are characterized by expression of the transcription factor Foxn1 and by cell surface expression of MTS24. These TEPC arise exclusively from progenitors originating from the anterior foregut endoderm during embryogenesis. Therefore, we hypothesized that common TEPC may be generated in-vitro from embryonic stem (ES) cells that have differentiated towards definitive endoderm. Currently, the mechanisms underlying commitment of definitive endoderm towards a thymic fate are unknown. In order to differentiate murine ES cells towards definitive endoderm and TEPC and to identify the factors involved in the commitment of endoderm towards a thymic fate we investigated the expression of MTS24 and of genes associated with thymic differentiation in ES-cell derived endoderm using a Gcs–GFP/Sox17–huCD25 reporter ES cell line. Culture of these GscgfpSox17huCD25 ES cells in the presence of Activin A resulted in a rapid induction of mesendodermal differentiation. After 6 days of culture the majority of cells differentiated towards mesoderm (Gsc+Sox17−, 60%) and definitive endoderm (GSC+Sox17+, 35%). Apart from the addition of Activin A, the use of low passage number ES-cells and a seeding density between 200–300 cells/cm2 were the most important factors determining efficient differentiation towards definitive endoderm. Addition of insulin or WNT-3a had no significant effect on differentiation, while usage of a high passage number of ES-cells and/or a high seeding density mainly promoted development of visceral endoderm. Real-time quantitative PCR of the definitive endoderm fraction of these cultures not only showed expression of genes associated with definitive endoderm and gut tube formation (i.e. Sox17, Foxa2, Hnf4a and TCF2) but also of genes associated with anterior foregut endoderm (i.e. Hhex, Pax9) and a low, but significant, expression of Foxn1. Analysis of MTS24 expression within these cultures showed the presence of this antigen on all three cell types. The percentage of cells expressing MTS24 was highest in visceral endoderm (30–50%) and lowest in mesoderm (5–10%). The expression was approximately 12% in definitive endoderm. We conclude that murine ES cells cultured in the presence of Activin A can efficiently differentiate towards gut-tube like endoderm, including anterior forgut endoderm, and that a fraction of the generated endoderm also expresses the surface marker MTS24, suggesting the generation of epithelial progenitors with phenotypic characteristics of TEPC.

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Roebroek, A. J., L. Umans, I. G. Pauli, et al. "Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin." Development 125, no. 24 (1998): 4863–76. http://dx.doi.org/10.1242/dev.125.24.4863.

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We have examined the role of Furin in postimplantation-stage mouse embryos by analyzing both the expression pattern of fur mRNA and the developmental consequences of a loss-of-function mutation at the fur locus. At early stages (day 7.5), fur mRNA is abundant in extraembryonic endoderm and mesoderm, anterior visceral endoderm, and in precardiac mesoderm. 1 day later fur is expressed throughout the heart tube and in the lateral plate mesoderm, notochordal plate and definitive gut endoderm. Embryos lacking Furin die between days 10.5 and 11.5, presumably due to hemodynamic insufficiency associated with severe ventral closure defects and the failure of the heart tube to fuse and undergo looping morphogenesis. Morphogenesis of the yolk sac vasculature is also abnormal, although blood islands and endothelial precursors form. Analysis of cardiac and endodermal marker genes shows that while both myocardial precursors and definitive endoderm cells are specified, their numbers and migratory properties are compromised. Notably, mutant embryos fail to undergo axial rotation, even though Nodal and eHand, two molecular markers of left-right asymmetry, are appropriately expressed. Overall, the present data identify Furin as an important activator of signals responsible for ventral closure and embryonic turning.

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Ang, S. L., A. Wierda, D. Wong, et al. "The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins." Development 119, no. 4 (1993): 1301–15. http://dx.doi.org/10.1242/dev.119.4.1301.

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Little is known about genes that govern the development of the definitive endoderm in mammals; this germ layer gives rise to the intestinal epithelium and various other cell types, such as hepatocytes, derived from the gut. The discovery that the rat hepatocyte transcription factor HNF3 is similar to the Drosophila forkhead gene, which plays a critical role in gut development in the fly, led us to isolate genes containing the HNF3/forkhead (HFH) domain that are expressed in mouse endoderm development. We recovered mouse HNF3 beta from an embryo cDNA library and found that the gene is first expressed in the anterior portion of the primitive streak at the onset of gastrulation, in a region where definitive endoderm first arises. Its expression persists in axial structures derived from the mouse equivalent of Hensen's node, namely definitive endoderm and notochord, and in the ventral region of the developing neural tube. Expression of the highly related gene, HNF3 alpha, appears to initiate later than HNF3 beta and is first seen in midline endoderm cells. Expression subsequently appears in notochord, ventral neural tube, and gut endoderm in patterns similar to HNF3 beta. Microscale DNA binding assays show that HNF3 proteins are detectable in the midgut at 9.5 days p.c. At later stages HNF3 mRNAs and protein are expressed strongly in endoderm-derived tissues such as the liver. HNF3 is also the only known hepatocyte-enriched transcription factor present in a highly de-differentiated liver cell line that retains the capacity to redifferentiate to the hepatic phenotype. Taken together, these studies suggest that HNF3 alpha and HNF3 beta are involved in both the initiation and maintenance of the endodermal lineage. We also discovered a novel HFH-containing gene, HFH-E5.1, that is expressed transiently in posterior ectoderm and mesoderm at the primitive streak stage, and later predominantly in the neural tube. HFH-E5.1 is highly similar in structure and expression profile to the Drosophila HFH gene FD4, suggesting that HFH family members have different, evolutionarily conserved roles in development.

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Tremblay, K. D., P. A. Hoodless, E. K. Bikoff, and E. J. Robertson. "Formation of the definitive endoderm in mouse is a Smad2-dependent process." Development 127, no. 14 (2000): 3079–90. http://dx.doi.org/10.1242/dev.127.14.3079.

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TGFbeta growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific cell surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast. Here we have generated chimeric embryos using lacZ-marked Smad2-deficient ES cells. Smad2 mutant cells extensively colonize ectodermal and mesodermal populations without disturbing normal development, but are not recruited into the definitive endoderm lineage during gastrulation. These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate. In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected. These results strongly suggest that other Smad(s) act downstream of Nodal signals in mesodermal populations. We found Smad2 and Smad3 transcripts both broadly expressed in derivatives of the epiblast. However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population.

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Martinez Barbera, J. P., M. Clements, P. Thomas, et al. "The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation." Development 127, no. 11 (2000): 2433–45. http://dx.doi.org/10.1242/dev.127.11.2433.

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The homeobox gene Hex is expressed in the anterior visceral endoderm (AVE) and rostral definitive endoderm of early mouse embryos. Later, Hex transcripts are detected in liver, thyroid and endothelial precursor cells. A null mutation was introduced into the Hex locus by homologous recombination in embryonic stem cells. Hex mutant embryos exhibit varying degrees of anterior truncation as well as liver and thyroid dysplasia. The liver diverticulum is formed but migration of hepatocytes into the septum transversum fails to occur. Development of the thyroid is arrested at the thyroid bud stage at 9.5 dpc. Brain defects are restricted to the rostral forebrain and have a caudal limit at the zona limitans intrathalamica, the boundary between dorsal and ventral thalamus. Analysis of Hex(−/−) mutants at early stages shows that the prospective forebrain ectoderm is correctly induced and patterned at 7.5 days post coitum (dpc), but subsequently fails to develop. AVE markers are expressed and correctly positioned but development of rostral definitive endoderm is greatly disturbed in Hex(−/−) embryos. Chimeric embryos composed of Hex(−/−) cells developing within a wild-type visceral endoderm show forebrain defects indicating that Hex is required in the definitive endoderm. All together, these results demonstrate that Hex function is essential in definitive endoderm for normal development of the forebrain, liver and thyroid gland.

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Sambathkumar, Rangarajan, Eric Kalo, Rob Van Rossom, Marijke M. Faas, Paul de Vos, and Catherine M. Verfaillie. "Epigenetic Induction of Definitive and Pancreatic Endoderm Cell Fate in Human Fibroblasts." Stem Cells International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7654321.

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Reprogramming can occur by the introduction of key transcription factors (TFs) as well as by epigenetic changes. We demonstrated that histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) combined with a chromatin remodeling medium (CRM) induced expression of a number of definitive endoderm and early and late pancreatic marker genes. When CRM was omitted, endoderm/pancreatic marker genes were not induced. Furthermore, treatment with DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (5AZA) CRM did not affect gene expression changes, and when 5AZA was combined with TSA, no further increase in gene expression of endoderm, pancreatic endoderm, and endocrine markers was seen over levels induced with TSA alone. Interestingly, TSA-CRM did not affect expression of pluripotency and hepatocyte genes but induced some mesoderm transcripts. Upon removal of TSA-CRM, the endoderm/pancreatic gene expression profile returned to baseline. Our findings underscore the role epigenetic modification in transdifferentiation of one somatic cell into another. However, full reprogramming of fibroblasts to β-cells will require combination of this approach with TF overexpression and/or culture of the partially reprogrammed cells under β-cell specific conditions.

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Nair, Gopika G., and Jon S. Odorico. "PTF1a Activity in Enriched Posterior Foregut Endoderm, but Not Definitive Endoderm, Leads to Enhanced Pancreatic Differentiation in anIn VitroMouse ESC-Based Model." Stem Cells International 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/6939438.

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Transcription factors are tools repetitively used by the embryo to generate a variety of lineages. Hence, their context of activation is an important determinant of their ability to specifically trigger certain cell fates, but not others. The context is also consequential when considering directing differentiation of embryonic stem cells (ESCs). In this study, we sought to assess the context of pancreatic transcription factor 1a (PTF1a) activation in reference to its propancreatic effects in mouse ESCs (mESCs). We hypothesized that an enriched endodermal population would respond to PTF1a and trigger the pancreatic program more effectively than a spontaneously differentiated population. Using anin vitromodel of pancreas development that we recently established, we found that inducing PTF1a in highly enriched definitive endoderm did not promote pancreatic differentiation but induction in more differentiated endoderm, specifically posterior foregut endoderm, did form pancreatic progenitors. These progenitors never underwent terminal differentiation to endocrine or acinar phenotype. However, a short 3D culture period, prior to PTF1a induction, led to the generation of monohormonal insulin+cells and amylase-expressing cells. Our findings suggest that enriched posterior foregut endoderm is competent to respond to PTF1a’s propancreatic activity; but a 3D culture environment is essential for terminal differentiation of pancreatic progenitors.

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Stark, K. L., J. A. McMahon, and A. P. McMahon. "FGFR-4, a new member of the fibroblast growth factor receptor family, expressed in the definitive endoderm and skeletal muscle lineages of the mouse." Development 113, no. 2 (1991): 641–51. http://dx.doi.org/10.1242/dev.113.2.641.

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We have used the polymerase chain reaction to clone from fetal cerebellar RNA a novel member of the fibroblast growth factor receptor family, FGFR-4. cDNAs encoding a full-length receptor were isolated and RNA expression examined in adult and fetal tissues by RNA blot analysis. Transcripts were detected in adult lung, liver and kidney and in fetal RNAs from 11.5 to 16.5 days post coitum (p.c.). In situ hybridization was performed to examine developmental expression. FGFR-4 RNA was expressed in definitive endoderm of the developing gut and extraembryonic endoderm of the yolk-sac from 8.5 to 14.5 days p.c. At early somite stages, FGFR-4 was also expressed in the myotomal component of the somite, and by 14.5 days p.c. in the myotomally derived skeletal muscle. No expression was seen at any stage in cardiac muscle. Several endodermal derivatives, the liver, lung and pancreas, expressed FGFR-4 at 14.5 days p.c. In addition, FGFR-4 RNA was detected in the adrenal cortex, collecting tubules of the kidney and condensing cartilage at this time. These results suggest that FGFR-4 is likely to have diverse roles in development, which may include regulation of definitive endoderm and skeletal muscle lineages.

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Ma, Risheng, Rauf Latif, and Terry F. Davies. "Thyrotropin-Independent Induction of Thyroid Endoderm from Embryonic Stem Cells by Activin A." Endocrinology 150, no. 4 (2008): 1970–75. http://dx.doi.org/10.1210/en.2008-1374.

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To model the differentiation of thyroid epithelial cells, we examined embryoid bodies derived from undifferentiated murine embryonic stem cells treated with activin A to induce endoderm differentiation, the germ layer from which thyroid cells occur. The resulting endodermal cells were then further exposed to TSH and/or IGF-I for up to 21 d. Oct-4 and REX1 expression, required to sustain stem cell self-renewal and pluripotency, were appropriately down-regulated, whereas GATA-4, and α-fetoprotein, both endodermal-specific markers, increased as the embryonic stem cells were exposed to activin A. By d 5 culture, TSH receptor (TSHR) and sodium iodide symporter (NIS) gene and protein expression were markedly induced. Cells isolated by the fluorescence-activated cell sorter simultaneously expressed not only TSHR and NIS proteins but also PAX8 mRNA, an expression pattern unique to thyroid cells and expected in committed thyroid progenitor cells. Such expression continued until d 21 with no influence seen by the addition of TSH or IGF-I. The sequence of gene expression changes observed in these experiments demonstrated the emergence of definitive thyroid endoderm. The activin A induction of thyroid-specific markers, NIS and TSHR, occurred in the absence of TSH stimulation, and, therefore, the emergence of thyroid endoderm in vitro paralleled the emergence of thyroid cells in TSHR-knockout mice. Activin A is clearly a major regulator of thyroid endoderm.

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Teo, A. K. K., S. J. Arnold, M. W. B. Trotter, et al. "Pluripotency factors regulate definitive endoderm specification through eomesodermin." Genes & Development 25, no. 3 (2011): 238–50. http://dx.doi.org/10.1101/gad.607311.

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Frumkin, A., Z. Rangini, A. Ben-Yehuda, Y. Gruenbaum, and A. Fainsod. "A chicken caudal homologue, CHox-cad, is expressed in the epiblast with posterior localization and in the early endodermal lineage." Development 112, no. 1 (1991): 207–19. http://dx.doi.org/10.1242/dev.112.1.207.

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CHox-cad is a chicken homeobox gene whose homeodomain is homologous to the Drosophila caudal and the murine Cdx1 genes. Based on sequence analysis of a 2.5 kb CHox-cad cDNA clone, we deduced that the primary translation product consists of 248 amino acids. Comparison between the cDNA and genomic clones revealed the presence of an intron within the CHox-cad homeodomain between amino acids 44 and 45. The onset of CHox-cad transcription correlates temporarily with the beginning of gastrulation. During primitive streak stages CHox-cad exhibits a caudally localized pattern of expression restricted to the epiblast and the primitive streak. At these stages, CHox-cad transcripts can also be detected in the definitive endoderm cells. Later in embryogenesis CHox-cad is expressed in the epithelial lining of the embryonic gut and yolk sac. After four days of chicken development, no CHox-cad transcripts could be detected. The early CHox-cad posterior expression in the germ layer undergoing gastrulation and its continuous expression in the early endodermal lineage raise the possibility of CHox-cad involvement in the establishment of the definitive endoderm.

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Dufort, D., L. Schwartz, K. Harpal, and J. Rossant. "The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis." Development 125, no. 16 (1998): 3015–25. http://dx.doi.org/10.1242/dev.125.16.3015.

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During early embryogenesis, the transcription factor HNF3beta is expressed in visceral and definitive endoderm, node, notochord and floorplate. A targeted mutation in the HNF3β gene results in the lack of a definitive node and notochord. Furthermore, lack of HNF3beta results in failure of proper primitive streak elongation. To address whether HNF3beta is required in visceral endoderm, we have used tetraploid embryo-ES cell aggregations to generate chimeric mouse embryos with wild-type visceral endoderm and homozygous mutant HNF3beta embryonic ectoderm or vice versa. Replacing the visceral endoderm of mutant HNF3beta embryos rescued proper primitive streak elongation and, conversely, mutant visceral endoderm imposed a severe embryonic-extraembryonic constriction on wild-type embryonic ectoderm. Restoration of normal streak morphogenesis was not sufficient to allow formation of the node and notochord in HNF3beta mutant embryos. Thus, our results demonstrate that HNF3beta has two separate roles in primitive streak formation. One is to act within the visceral endoderm to promote proper streak morphogenesis. The second is autonomous to the node and its precursors and involves specification of node and notochord cell fates. HNF3beta mutant embryos rescued for the embryonic-extraembryonic constriction developed further than mutant embryos, allowing examination of later roles for HNF3beta. We show that such mutant embryos lack foregut and midgut endoderm. In addition, left-right asymmetry is affected in the mutant embryos.

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Pierre, Monique S., and Mervin Yoder. "Deficiency in GATA-4 or GATA-6 Diminishes Definitive Hematopoiesis in Murine Embryonic Stem Cell Derived Embryoid Bodies." Blood 110, no. 11 (2007): 2230. http://dx.doi.org/10.1182/blood.v110.11.2230.2230.

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Abstract Formation of mesoderm derived blood islands in the mouse embryonic yolk sac requires the presence of visceral endoderm (VE) and VE derived factors. Murine embryonic stem (ES) cells can be differentiated into embryoid bodies (EBs) which serve as an in vitro model recapitulating many embryonic developmental processes, including formation of early hematopoietic cells. Previous investigators have reported that differentiation of ES cells deficient in either GATA-4 or GATA-6 results in EBs with disrupted differentiation of visceral endoderm and defective blood island formation. In the current study, we have compared GATA-4 and GATA-6 null ES cell derived EBs to wild-type EBs in their ability to commit to early hematopoietic lineages using hematopoietic progenitor colony assays, and used RT-PCR to assess the expression of endoderm genes. As expected, we observed differences in expression of endoderm genes in wild-type and GATA-4 or GATA-6 null EBs. Blast colony forming cell assays and primitive erythroid progenitor assays revealed no difference in the ability of wild-type and GATA-4 or GATA-6 null EBs to form hemangioblast or primitive erythroid progenitor colonies. In contrast, comparisons of definitive hematopoietic progenitor colonies from day 8, 9 and 10 GATA-4 and GATA-6 null EBs revealed a significant reduction in colony numbers at day 8 (p-values &lt; 0.05) compared to wild-type. Strikingly, definitive progenitor colony numbers are rescued nearly to wild-type levels after the addition of the visceral endoderm derived factor vascular endothelial growth factor (VEGF) during EB differentiation. Furthermore, this rescue response can be blocked by the addition of soluble Flk-1 (VEGF receptor) to EB cultures. These results suggest that GATA-4 and GATA-6 transcription factors and/or visceral endoderm are not necessary for hemangioblast, primitive erythroid, or definitive progenitor emergence from EBs but play a role in definitive progenitor expansion in EBs.

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Illing, Anett, Marianne Stockmann, Narasimha Swamy Telugu, et al. "Definitive Endoderm Formation from Plucked Human Hair-Derived Induced Pluripotent Stem Cells and SK Channel Regulation." Stem Cells International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/360573.

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Pluripotent stem cells present an extraordinary powerful tool to investigate embryonic development in humans. Essentially, they provide a unique platform for dissecting the distinct mechanisms underlying pluripotency and subsequent lineage commitment. Modest information currently exists about the expression and the role of ion channels during human embryogenesis, organ development, and cell fate determination. Of note, small and intermediate conductance, calcium-activated potassium channels have been reported to modify stem cell behaviour and differentiation. These channels are broadly expressed throughout human tissues and are involved in various cellular processes, such as the after-hyperpolarization in excitable cells, and also in differentiation processes. To this end, human induced pluripotent stem cells (hiPSCs) generated from plucked human hair keratinocytes have been exploitedin vitroto recapitulate endoderm formation and, concomitantly, used to map the expression of the SK channel (SKCa) subtypes over time. Thus, we report the successful generation of definitive endoderm from hiPSCs of ectodermal origin using a highly reproducible and robust differentiation system. Furthermore, we provide the first evidence that SKCas subtypes are dynamically regulated in the transition from a pluripotent stem cell to a more lineage restricted, endodermal progeny.

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Shiraki, Nobuaki, Yuichiro Higuchi, and Shoen Kume. "Guiding ES cell differentiation into the definitive endoderm lineages." Inflammation and Regeneration 30, no. 2 (2010): 109–14. http://dx.doi.org/10.2492/inflammregen.30.109.

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Shiraki, Nobuaki, Seiko Harada, Soichiro Ogaki, Kazuhiko Kume, and Shoen Kume. "Identification of DAF1/CD55, a Novel Definitive Endoderm Marker." Cell Structure and Function 35, no. 2 (2010): 73–80. http://dx.doi.org/10.1247/csf.10004.

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Candiello, Joseph, Thomas Richardson, Kimaya Padgaonkar, Keith Task, Prashant N. Kumta, and Ipsita Banerjee. "Alginate encapsulation of chitosan nanoparticles: a viable alternative to soluble chemical signaling in definitive endoderm induction of human embryonic stem cells." Journal of Materials Chemistry B 4, no. 20 (2016): 3575–83. http://dx.doi.org/10.1039/c5tb02428e.

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Knoetgen, H., C. Viebahn, and M. Kessel. "Head induction in the chick by primitive endoderm of mammalian, but not avian origin." Development 126, no. 4 (1999): 815–25. http://dx.doi.org/10.1242/dev.126.4.815.

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Different types of endoderm, including primitive, definitive and mesendoderm, play a role in the induction and patterning of the vertebrate head. We have studied the formation of the anterior neural plate in chick embryos using the homeobox gene GANF as a marker. GANF is first expressed after mesendoderm ingression from Hensen's node. We found that, after transplantation, neither the avian hypoblast nor the anterior definitive endoderm is capable of GANF induction, whereas the mesendoderm (young head process, prechordal plate) exhibits a strong inductive potential. GANF induction cannot be separated from the formation of a proper neural plate, which requires an intact lower layer and the presence of the prechordal mesendoderm. It is inhibited by BMP4 and promoted by the presence of the BMP antagonist Noggin. In order to investigate the inductive potential of the mammalian visceral endoderm, we used rabbit embryos which, in contrast to mouse embryos, allow the morphological recognition of the prospective anterior pole in the living, pre-primitive-streak embryo. The anterior visceral endoderm from such rabbit embryos induced neuralization and independent, ectopic GANF expression domains in the area pellucida or the area opaca of chick hosts. Thus, the signals for head induction reside in the anterior visceral endoderm of mammals whereas, in birds and amphibia, they reside in the prechordal mesendoderm, indicating a heterochronic shift of the head inductive capacity during the evolution of mammalia.

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Kulkeaw, Kasem, Alisa Tubsuwan, Nongnat Tongkrajang, and Narisara Whangviboonkij. "Generation of human liver organoids from pluripotent stem cell-derived hepatic endoderms." PeerJ 8 (October 19, 2020): e9968. http://dx.doi.org/10.7717/peerj.9968.

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Background The use of a personalized liver organoid derived from human-induced pluripotent stem cells (HuiPSCs) is advancing the use of in vitro disease models for the design of specific, effective therapies for individuals. Collecting patient peripheral blood cells for HuiPSC generation is preferable because it is less invasive; however, the capability of blood cell-derived HuiPSCs for hepatic differentiation and liver organoid formation remains uncertain. Moreover, the currently available methods for liver organoid formation require a multistep process of cell differentiation or a combination of hepatic endodermal, endothelial and mesenchymal cells, which is a major hurdle for the application of personalized liver organoids in high-throughput testing of drug toxicity and safety. To demonstrate the capability of blood cell-derived HuiPSCs for liver organoid formation without support from endothelial and mesenchymal cells. Methods The peripheral blood-derived HuiPSCs first differentiated into hepatic endoderm (HE) in two-dimensional (2D) culture on Matrigel-coated plates under hypoxia for 10 days. The HE was then collected and cultured in 3D culture using 50% Matrigel under ambient oxygen. The maturation of hepatocytes was further induced by adding hepatocyte growth medium containing HGF and oncostatin M on top of the 3D culture and incubating the culture for an additional 12–17 days. The function of the liver organoids was assessed using expression analysis of hepatocyte-specific gene and proteins. Albumin (ALB) synthesis, glycogen and lipid storage, and metabolism of indocyanine were evaluated. The spatial distribution of albumin was examined using immunofluorescence and confocal microscopy. Results CD34+ hematopoietic cell-derived HuiPSCs were capable of differentiating into definitive endoderm expressing SOX17 and FOXA2, hepatic endoderm expressing FOXA2, hepatoblasts expressing AFP and hepatocytes expressing ALB. On day 25 of the 2D culture, cells expressed SOX17, FOXA2, AFP and ALB, indicating the presence of cellular heterogeneity. In contrast, the hepatic endoderm spontaneously formed a spherical, hollow structure in a 3D culture of 50% Matrigel, whereas hepatoblasts and hepatocytes could not form. Microscopic observation showed a single layer of polygonal-shaped cells arranged in a 3D structure. The hepatic endoderm-derived organoid synthesis ALB at a higher level than the 2D culture but did not express definitive endoderm-specific SOX17, indicating the greater maturity of the hepatocytes in the liver organoids. Confocal microscopic images and quantitative ELISA confirmed albumin synthesis in the cytoplasm of the liver organoid and its secretion. Overall, 3D culture of the hepatic endoderm is a relatively fast, simple, and less laborious way to generate liver organoids from HuiPSCs that is more physiologically relevant than 2D culture.

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Thomas, P. Q., A. Brown, and R. S. Beddington. "Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors." Development 125, no. 1 (1998): 85–94. http://dx.doi.org/10.1242/dev.125.1.85.

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The divergent homeobox gene Hex exhibits three notable expression patterns during early mouse development. Initially Hex is expressed in the primitive endoderm of the implanting blastocyst but by 5.5 dpc its transcripts are present only in a small patch of visceral endoderm at the distal tip of the egg cylinder. Lineage analysis shows that these cells move unilaterally to assume an anterior position while continuing to express Hex. The primitive streak forms on the opposite side of the egg cylinder from this anterior Hex expression domain approximately 24 hours after the initial anterior movement of the distal visceral endoderm. Thus, Hex expression marks the earliest unequivocal molecular anteroposterior asymmetry in the mouse embryo and indicates that the anteroposterior axis of the embryo develops from conversion of a proximodistal asymmetry established in the primitive endoderm lineage. Subsequently, Hex is expressed in the earliest definitive endoderm to emerge from the streak and its expression within the gut strongly suggests that the ventral foregut is derived from the most anterior definitive endoderm and that the liver is probably the most anterior gut derivative. Hex is also an early marker of the thyroid primordium. Within the mesoderm, Hex is transiently expressed in the nascent blood islands of the visceral yolk sac and later in embryonic angioblasts and endocardium. Comparison with flk-1 (T. P. Yamaguchi et al., Development 118, 489–498, 1993) expression indicates that Hex is also an early marker of endothelial precursors but its expression in this progenitor population is much more transient than that of flk-1, being downregulated once endothelial cell differentiation commences.

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Liu, Szu-Hsiu, and Lain-Tze Lee. "Efficient Differentiation of Mouse Embryonic Stem Cells into Insulin-Producing Cells." Experimental Diabetes Research 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/201295.

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Embryonic stem (ES) cells are a potential source of a variety of differentiated cells for cell therapy, drug discovery, and toxicology screening. Here, we present an efficacy strategy for the differentiation of mouse ES cells into insulin-producing cells (IPCs) by a two-step differentiation protocol comprising of (i) the formation of definitive endoderm in monolayer culture by activin A, and (ii) this monolayer endoderm being induced to differentiate into IPCs by nicotinamide, insulin, and laminin. Differentiated cells can be obtained within approximately 7 days. The differentiation IPCs combined application of RT-PCR, ELISA, and immunofluorescence to characterize phenotypic and functional properties. In our study, we demonstrated that IPCs produced pancreatic transcription factors, endocrine progenitor marker, definitive endoderm, pancreaticβ-cell markers, and Langerhansαandδcells. The IPCs released insulin in a manner that was dose dependent upon the amount of glucose added. These techniques may be able to be applied to human ES cells, which would have very important ramifications for treating human disease.

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Mahaddalkar, Pallavi U., Katharina Scheibner, Sandra Pfluger та ін. "Generation of pancreatic β cells from CD177+ anterior definitive endoderm". Nature Biotechnology 38, № 9 (2020): 1061–72. http://dx.doi.org/10.1038/s41587-020-0492-5.

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Kubo, A. "Development of definitive endoderm from embryonic stem cells in culture." Development 131, no. 7 (2004): 1651–62. http://dx.doi.org/10.1242/dev.01044.

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McKnight, Kristen D., Juan Hou, and Pamela A. Hoodless. "Dynamic expression ofThyrotropin-releasing hormone in the mouse definitive endoderm." Developmental Dynamics 236, no. 10 (2007): 2909–17. http://dx.doi.org/10.1002/dvdy.21313.

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Taylor-Weiner, Hermes, Jean E. Schwarzbauer, and Adam J. Engler. "Defined extracellular matrix components are necessary for definitive endoderm induction." STEM CELLS 31, no. 10 (2013): 2084–94. http://dx.doi.org/10.1002/stem.1453.

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D'Amour, Kevin A., Alan D. Agulnick, Susan Eliazer, Olivia G. Kelly, Evert Kroon, and Emmanuel E. Baetge. "Efficient differentiation of human embryonic stem cells to definitive endoderm." Nature Biotechnology 23, no. 12 (2005): 1534–41. http://dx.doi.org/10.1038/nbt1163.

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Hassan, Ali S., Juan Hou, Wei Wei, and Pamela A. Hoodless. "Expression of two novel transcripts in the mouse definitive endoderm." Gene Expression Patterns 10, no. 2-3 (2010): 127–34. http://dx.doi.org/10.1016/j.gep.2010.02.001.

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Li, Shengbiao, Qingsong Huang, Jianwen Mao та Qiuhong Li. "TGFβ-dependent mitochondrial biogenesis is activated during definitive endoderm differentiation". In Vitro Cellular & Developmental Biology - Animal 56, № 5 (2020): 378–85. http://dx.doi.org/10.1007/s11626-020-00442-9.

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Constam, D. B., and E. J. Robertson. "Tissue-specific requirements for the proprotein convertase furin/SPC1 during embryonic turning and heart looping." Development 127, no. 2 (2000): 245–54. http://dx.doi.org/10.1242/dev.127.2.245.

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Furin, the mammalian prototype of a family of serine proteases, is required for ventral closure and axial rotation, and formation of the yolk sac vasculature. Here we show additionally that left-sided expression of pitx2 and lefty-2 are also perturbed in Furin-deficient embryos. These tissue abnormalities are preceded by a marked delay in the expansion of the definitive endoderm during gastrulation. Using a chimera approach, we show that Furin activity is required in epiblast derivatives, including the primitive heart, gut and extraembryonic mesoderm, whereas it is nonessential in the visceral endoderm. Thus, chimeric embryos, derived by injecting wild-type embryonic stem (ES) cells into fur(−/−) blastocysts, develop normally until at least 9.5 d.p.c. In contrast, Furin-deficient chimeras developing in the context of wild-type visceral endoderm fail to undergo ventral closure, axial rotation and yolk sac vascularization. Fur(−/−) cells are recruited into all tissues examined, including the yolk sac vasculature and the midgut, even though these structures fail to form in fur mutants. The presence of wild-type cells in the gut strikingly correlates with the ability of chimeric embryos to undergo turning. Overall, we conclude that Furin activity is essential in both extraembryonic and precardiac mesoderm, and in definitive endoderm derivatives.

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Chalmers, A. D., and J. M. Slack. "The Xenopus tadpole gut: fate maps and morphogenetic movements." Development 127, no. 2 (2000): 381–92. http://dx.doi.org/10.1242/dev.127.2.381.

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We have produced a comprehensive fate map showing where the organs of the gut and respiratory system are derived from in the early Xenopus laevis endoderm. We also show the origin of the associated smooth muscle layer on a separate fate map. Comparison of the two maps shows that for most organs of the gut the prospective epithelium and smooth muscle do not overlie each other in the early embryo but come together at a later stage. These fate maps should be useful for future studies into endoderm specification. It was not previously known how the elongation of the endoderm occurs, how the single-layered dorsal and many-layered ventral endoderm gives rise to the single layered epithelium, and whether or not the archenteron cavity actually gives rise to the gut lumen. Using a variety of labelling procedures we show firstly, that radial intercalation occurs in the gut transforming a short thick tube into a long thin tube; secondly, that the archenteron lining does not become the definitive gut lumen. Instead the archenteron cavity almost closes at tailbud stages before providing a nucleus for the definitive gut cavity, which opens up during elongation. Based on this work we present a model explaining the morphogenesis of the gut.

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Semb, Henrik. "Definitive endoderm: a key step in coaxing human embryonic stem cells into transplantable β-cells". Biochemical Society Transactions 36, № 3 (2008): 272–75. http://dx.doi.org/10.1042/bst0360272.

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Using the Edmonton protocol, a number of patients with Type 1 diabetes mellitus have remained insulin-independent for prolonged periods of time. In spite of this success, transplantation of islets from cadaver donors will remain a therapy for very few patients owing to a lack of donors. Thus, if cell therapy should be widely available, it will require an unlimited source of cells to serve as a ‘biological’ insulin pump. At this time, the development of β-cells from hESCs (human embryonic stem cells) has emerged as the most attractive alternative. It is envisioned that ultimate success of an in vitro approach to programme hESCs into β-cells will depend on the ability, at least to a certain degree, to sequentially reproduce the individual steps that characterizes normal β-cell ontogenesis during fetal pancreatic development, including definitive endoderm from which all gastrointestinal organs, including the pancreas, originate. In the present article, differentiation of hESCs into putative definitive endodermal cell types is reviewed.

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Cascio, S., and K. S. Zaret. "Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation." Development 113, no. 1 (1991): 217–25. http://dx.doi.org/10.1242/dev.113.1.217.

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Previous studies with embryonic tissue explants showed that cellular interactions with mesenchyme are required for endodermal cells to differentiate into hepatocytes. However, these studies assayed hepatocyte characteristics that were evident after days of culture, leaving open the question of whether the primary inductive interactions initiated hepatocyte differentiation, or whether subsequent steps, such as may occur during cell aggregation to form the liver, were necessary. Using the technique of in situ hybridization, we find that serum albumin mRNA, a liver-specific gene product, is first detected in hepatic precursor cells of the endoderm as early as 9.5 days of mouse embryo development, a full day prior to cell aggregation and liver formation. The endodermal cells express albumin mRNA upon migration into strands of connective tissue matrix within mesenchyme. Thus, the onset of differentiation of the endoderm is coincident with its interaction with mesenchyme. Early albumin transcripts are initiated at the same site of the albumin promoter as in adult hepatocytes, suggesting that at least a subset of the transcription factors that control albumin transcription in the adult may be involved in executing the early steps of hepatic determination. We also observe a sharp increase in albumin mRNA levels shortly after the definitive formation of the liver, apparently reflecting cell interactions that enhance hepatocyte differentiation. Hepatocyte differentiation is therefore similar in several respects to pancreatic exocrine cell development, and may represent a general pattern for gut-derived tissues. For both cell types, early interactions with mesenchyme are coincident with the initial expression of differentiated gene products at a low level in proliferating endoderm, and the initial pattern of expression is amplified upon organ formation.

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Toivonen, Sanna, Karolina Lundin, Diego Balboa, et al. "Activin A and Wnt-dependent specification of human definitive endoderm cells." Experimental Cell Research 319, no. 17 (2013): 2535–44. http://dx.doi.org/10.1016/j.yexcr.2013.07.007.

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Morrison, Gillian M., Ifigenia Oikonomopoulou, Rosa Portero Migueles, et al. "Anterior Definitive Endoderm from ESCs Reveals a Role for FGF Signaling." Cell Stem Cell 3, no. 4 (2008): 402–15. http://dx.doi.org/10.1016/j.stem.2008.07.021.

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Villegas, Santiago Nahuel, Ifigenia Oikonomoulu, Gilliam Morrison, Shamit Soneji, Tariq Enver, and Joshua Brickman. "14-P003 Identification of genes expressed in the anterior definitive endoderm." Mechanisms of Development 126 (August 2009): S239—S240. http://dx.doi.org/10.1016/j.mod.2009.06.622.

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Ghanian, Mohammad Hossein, Zahra Farzaneh, Jalal Barzin, et al. "Nanotopographical control of human embryonic stem cell differentiation into definitive endoderm." Journal of Biomedical Materials Research Part A 103, no. 11 (2015): 3539–53. http://dx.doi.org/10.1002/jbm.a.35483.

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Guiu, Jordi, and Kim B. Jensen. "From Definitive Endoderm to Gut—a Process of Growth and Maturation." Stem Cells and Development 24, no. 17 (2015): 1972–83. http://dx.doi.org/10.1089/scd.2015.0017.

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Karmakar, Soham, Lu Deng, Xi C. He, and Linheng Li. "Intestinal epithelial regeneration: active versus reserve stem cells and plasticity mechanisms." American Journal of Physiology-Gastrointestinal and Liver Physiology 318, no. 4 (2020): G796—G802. http://dx.doi.org/10.1152/ajpgi.00126.2019.

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The gastrointestinal system is arguably one of the most complicated developmental systems in a multicellular organism, as it carries out at least four major functions: digestion of food, absorption of nutrients, excretion of hormones, and defense against pathogens. Anatomically, the fetal gut has a tubular structure with an outer layer of smooth muscle derived from lateral splanchnic mesoderm and an inner lining of epithelium derived from the definitive endoderm. During morphogenesis of the gut tube, the definitive endoderm transforms into a primitive gut tube with a foregut, midgut, and hindgut. During the course of further development, the midgut gives rise to the small and proximal large intestine and the hindgut gives rise to the distal large intestine and rectum. The small intestine is subdivided into three parts: duodenum, jejunum, and ileum, whereas the large intestine is subdivided into the cecum, colon, and rectum.

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Tan, Mengtian, Lai Jiang, Yinglei Li, and Wei Jiang. "Dual Inhibition of BMP and WNT Signals Promotes Pancreatic Differentiation from Human Pluripotent Stem Cells." Stem Cells International 2019 (December 1, 2019): 1–15. http://dx.doi.org/10.1155/2019/5026793.

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Pathological or functional loss of pancreatic beta cells is the cause of diabetes. Understanding how signaling pathways regulate pancreatic lineage and searching for combinations of signal modulators to promote pancreatic differentiation will definitely facilitate the robust generation of functional beta cells for curing hyperglycemia. In this study, we first tested the effect of several potent BMP inhibitors on pancreatic differentiation using human embryonic stem cells. Next, we examined the endodermal lineage bias upon potent BMP inhibitor treatment and further checked the crosstalk between signal pathways governing endodermal lineage determination. Furthermore, we improved current pancreatic differentiation system based on the signaling pathway study. Finally, we used human-induced pluripotent stem cells to validate our finding. We found BMP inhibitors indeed not only blocked hepatic lineage but also impeded intestinal lineage from human definitive endoderm unexpectedly. Signaling pathway analysis indicated potent BMP inhibitor resulted in the decrease of WNT signal activity and inhibition of WNT could contribute to the improved pancreatic differentiation. Herein, we combined the dual inhibition of BMP and WNT signaling and greatly enhanced human pancreatic progenitor differentiation as well as beta cell generation from both embryonic stem cells and induced pluripotent stem cells. Conclusively, our present work identified the crosstalk between the BMP and WNT signal pathways during human endoderm patterning and pancreas specification, and provided an improved in vitro pancreatic directed differentiation protocol from human pluripotent stem cells.

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Onyshchenko, Mykola I., Igor G. Panyutin, Irina V. Panyutin, and Ronald D. Neumann. "Stimulation of Cultured H9 Human Embryonic Stem Cells with Thyroid Stimulating Hormone Does Not Lead to Formation of Thyroid-Like Cells." Stem Cells International 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/634914.

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The sodium-iodine symporter (NIS) is expressed on the cell membrane of many thyroid cancer cells, and is responsible for the radioactive iodine accumulation. However, treatment of anaplastic thyroid cancer is ineffective due to the low expression of NIS on cell membranes of these tumor cells. Human embryonic stem cells (ESCs) provide a potential vehicle to study the mechanisms of NIS expression regulation during differentiation. Human ESCs were maintained on feeder-independent culture conditions. RT-qPCR and immunocytochemistry were used to study differentiation marker expression,125I uptake to study NIS function. We designed a two-step protocol for human ESC differentiation into thyroid-like cells, as was previously done for mouse embryonic stem cells. First, we obtained definitive endoderm from human ESCs. Second, we directed differentiation of definitive endoderm cells into thyroid-like cells using various factors, with thyroid stimulating hormone (TSH) as the main differentiating factor. Expression of pluripotency, endoderm and thyroid markers and125I uptake were monitored throughout the differentiation steps. These approaches did not result in efficient induction of thyroid-like cells. We conclude that differentiation of human ESCs into thyroid cells cannot be induced by TSH media supplementation alone and most likely involves complicated developmental patterns that are yet to be understood.

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Korostylev, Alexander, Pallavi U. Mahaddalkar, Oliver Keminer, et al. "A high-content small molecule screen identifies novel inducers of definitive endoderm." Molecular Metabolism 6, no. 7 (2017): 640–50. http://dx.doi.org/10.1016/j.molmet.2017.04.009.

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Sherwood, Richard I., Cristian Jitianu, Ondine Cleaver, et al. "Prospective isolation and global gene expression analysis of definitive and visceral endoderm." Developmental Biology 304, no. 2 (2007): 541–55. http://dx.doi.org/10.1016/j.ydbio.2007.01.011.

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McKnight, Kristen D., and Pamela A. Hoodless. "Thyrotropin-releasing hormone precursor—A novel marker of the mouse definitive endoderm." Developmental Biology 306, no. 1 (2007): 403. http://dx.doi.org/10.1016/j.ydbio.2007.03.609.

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Taylor-Weiner, H., N. Ravi, and A. J. Engler. "Traction forces mediated by integrin signaling are necessary for definitive endoderm specification." Journal of Cell Science 128, no. 10 (2015): 1961–68. http://dx.doi.org/10.1242/jcs.166157.

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Sui, Lina, Luc Bouwens, and Josué K. Mfopou. "Signaling pathways during maintenance and definitive endoderm differentiation of embryonic stem cells." International Journal of Developmental Biology 57, no. 1 (2013): 1–12. http://dx.doi.org/10.1387/ijdb.120115ls.

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Bogacheva, Mariia S., Sofia Khan, Liisa K. Kanninen, Marjo Yliperttula, Alan W. Leung, and Yan-Ru Lou. "Differences in definitive endoderm induction approaches using growth factors and small molecules." Journal of Cellular Physiology 233, no. 4 (2017): 3578–89. http://dx.doi.org/10.1002/jcp.26214.

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Lewis, Samara L., and Patrick P. L. Tam. "Definitive endoderm of the mouse embryo: Formation, cell fates, and morphogenetic function." Developmental Dynamics 235, no. 9 (2006): 2315–29. http://dx.doi.org/10.1002/dvdy.20846.

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Journal articles on the topic 'Definitive endoderm'

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