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- W2895524207 abstract "Human pluripotent stem cell (hPSC)-derived organoids can reveal important principles underlying tissue development. In this issue of Cell Stem Cell, Zhang et al., 2018Zhang Y. Yang Y. Jiang M. Huang S.X. Zhang W. Alam D.A. Danopoulos S. Mori M. Chen Y.-W. Balasubramanian R. et al.3D modeling of esophageal development using human PSC-derived basal progenitors reveals a critical role for Notch signaling.Cell Stem Cell. 2018; 23 (this issue): 516-529Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and Trisno et al., 2018Trisno S.L. Philo K.E.D. McCracken K.W. Cata E.M. Ruiz-Torres S. Rankin S.A. Han L. Nasr T. Chatuvedi P. Rothenberg M.E. et al.Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification.Cell Stem Cell. 2018; 23 (this issue): 501-515Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar establish protocols for generating esophageal epithelial cells and 3D stratified epithelium from hPSCs, revealing roles for key signaling pathways and how they are controlled by critical transcription factors. Human pluripotent stem cell (hPSC)-derived organoids can reveal important principles underlying tissue development. In this issue of Cell Stem Cell, Zhang et al., 2018Zhang Y. Yang Y. Jiang M. Huang S.X. Zhang W. Alam D.A. Danopoulos S. Mori M. Chen Y.-W. Balasubramanian R. et al.3D modeling of esophageal development using human PSC-derived basal progenitors reveals a critical role for Notch signaling.Cell Stem Cell. 2018; 23 (this issue): 516-529Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and Trisno et al., 2018Trisno S.L. Philo K.E.D. McCracken K.W. Cata E.M. Ruiz-Torres S. Rankin S.A. Han L. Nasr T. Chatuvedi P. Rothenberg M.E. et al.Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification.Cell Stem Cell. 2018; 23 (this issue): 501-515Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar establish protocols for generating esophageal epithelial cells and 3D stratified epithelium from hPSCs, revealing roles for key signaling pathways and how they are controlled by critical transcription factors. The generation of epithelial structures from human pluripotent stem cells (hPSCs) provides a foundation for new insights into fundamental mechanisms underlying tissue formation as well as windows for studying disease etiology and potential therapeutics. Studies of the esophageal epithelium would benefit also from such platforms as a basis to integrate insights from developmental biology into normal homeostasis and disease pathophysiology. In this issue of Cell Stem Cell, Zhang et al., 2018Zhang Y. Yang Y. Jiang M. Huang S.X. Zhang W. Alam D.A. Danopoulos S. Mori M. Chen Y.-W. Balasubramanian R. et al.3D modeling of esophageal development using human PSC-derived basal progenitors reveals a critical role for Notch signaling.Cell Stem Cell. 2018; 23 (this issue): 516-529Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and Trisno et al., 2018Trisno S.L. Philo K.E.D. McCracken K.W. Cata E.M. Ruiz-Torres S. Rankin S.A. Han L. Nasr T. Chatuvedi P. Rothenberg M.E. et al.Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification.Cell Stem Cell. 2018; 23 (this issue): 501-515Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar take orthogonal approaches for deriving three-dimensional (3D) tissues from hPSCs that recapitulate esophageal development and morphology and utilize them to functionally interrogate the roles of candidate factors in tissue specification and formation. The lungs and esophagus are both derived from foregut endoderm. Partitions between these organs are evident at approximately 4–6 weeks in the human embryo and at embryonic (E) day 9.5–11.5 in the mouse. In the latter, a dorsoventral gradient of Bmp and Wnt signaling restricts expression of Nkx2.1 to the ventral aspect or pulmonary anlagen of the foregut endoderm and Sox2 expression to the dorsal aspect or esophageal anlagen of the foregut endoderm (Que et al., 2007Que J. Okubo T. Goldenring J.R. Nam K.T. Kurotani R. Morrisey E.E. Taranova O. Pevny L.H. Hogan B.L. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.Development. 2007; 134: 2521-2531Crossref PubMed Scopus (388) Google Scholar), with each factor driving acquisition of its associated tissue identity and mutually repressing the other (Morrisey and Rustgi, 2018Morrisey E.E. Rustgi A.K. The lung and esophagus: developmental and regenerative overlap.Trends Cell Biol. 2018; 28: 738-748Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Esophageal specification is thus repressed through Bmp and Wnt signaling, whereas Sonic hedgehog (SHH) and retinoic acid (RA) signaling drive expansion of embryonic esophagus and lung (Morrisey and Rustgi, 2018Morrisey E.E. Rustgi A.K. The lung and esophagus: developmental and regenerative overlap.Trends Cell Biol. 2018; 28: 738-748Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Initially, the esophageal epithelium is a simple layer of columnar cells, perhaps representing the remnant of a respiratory epithelium. Thereafter, esophageal epithelial cells stratify to yield a multilayered squamous epithelium. Sox2 is an important regulator of epithelial basal cell formation, and Trp63 has an equally important role as loss of Trp63 blocks the transition from a single columnar epithelium to a multilayered squamous epithelium. In the mature esophagus, basal cells continuously renew to give rise to transit-amplifying cells or suprabasal cells, which then terminally differentiate in the superficial squamous compartment and desquamate in the lumen. Importantly, the mouse lumenal surface is keratinized whereas the human lumenal surface is not. The proliferation-differentiation gradient is believed to be maintained through a subset of basal cells that have properties of stem cells (Giroux et al., 2017Giroux V. Lento A.A. Islam M. Pitarresi J.R. Kharbanda A. Hamilton K.E. Whelan K.A. Long A. Rhoades B. Tang Q. et al.Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration.J. Clin. Invest. 2017; 127: 2378-2391Crossref PubMed Scopus (57) Google Scholar) as well as Notch signaling, as Notch1 seems to promote basal cell proliferation whereas Notch3 fosters differentiation (Ohashi et al., 2010Ohashi S. Natsuizaka M. Yashiro-Ohtani Y. Kalman R.A. Nakagawa M. Wu L. Klein-Szanto A.J. Herlyn M. Diehl J.A. Katz J.P. et al.NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network.Gastroenterology. 2010; 139: 2113-2123Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). In addition, factors extrinsic to the esophageal epithelium also have key roles in esophageal epithelial specification and maintenance. For example, in mouse models, mutations in Foxf1 or Shh (Litingtung et al., 1998Litingtung Y. Lei L. Westphal H. Chiang C. Sonic hedgehog is essential to foregut development.Nat. Genet. 1998; 20: 58-61Crossref PubMed Scopus (573) Google Scholar) result in esophageal atresia or trachea-esophageal fistula. Loss of the BARX1 transcription factor promotes induction of Wnt signaling, and mutations in Barx1 also result in esophageal atresia or trachea-esophageal fistula (Woo et al., 2011Woo J. Miletich I. Kim B.M. Sharpe P.T. Shivdasani R.A. Barx1-mediated inhibition of Wnt signaling in the mouse thoracic foregut controls tracheo-esophageal septation and epithelial differentiation.PLoS ONE. 2011; 6: e22493Crossref PubMed Scopus (54) Google Scholar) Building upon success in other tissues, Zhang et al., 2018Zhang Y. Yang Y. Jiang M. Huang S.X. Zhang W. Alam D.A. Danopoulos S. Mori M. Chen Y.-W. Balasubramanian R. et al.3D modeling of esophageal development using human PSC-derived basal progenitors reveals a critical role for Notch signaling.Cell Stem Cell. 2018; 23 (this issue): 516-529Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and Trisno et al., 2018Trisno S.L. Philo K.E.D. McCracken K.W. Cata E.M. Ruiz-Torres S. Rankin S.A. Han L. Nasr T. Chatuvedi P. Rothenberg M.E. et al.Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification.Cell Stem Cell. 2018; 23 (this issue): 501-515Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar develop techniques to convert hPSC-derived anterior foregut endoderm into an esophageal epithelium. While both generate 3D stratified epithelial structures, these two groups leveraged molecular knowledge of epithelial specification in significantly different ways. Zhang et al. used a published protocol to differentiate RUES2 human embryonic stem cells (hESCs) into anterior forget endoderm with Activin A, BMP4, FGF2, and a Rock inhibitor. Then, Noggin activation and TGFβ inhibition were implemented, followed in the next specification step by TGFβ inhibition and WNT/β-catenin inhibition. This was accompanied by increased expression of esophageal markers such as FOXA2 and, eventually, SOX2, Trp63, PAX9, and FOXE1. Key to the outlined approach is the dual inhibition of BMP and WNT signaling that has been noted to be critical in esophageal development. The approach was also validated in additional hPSC lines, and putative human esophageal progenitor cells expressed characteristic proteins such as KRT5, KRT7, KRT13, INVOLUCRIN (INV), and the aforementioned transcriptional factors. The esophageal progenitor cells were purified by FACS based upon EPCAM and ITGβ4 expression. These cells formed 3D organoids and could reconstitute also the stratified squamous epithelium in 3D organotypic culture. These complementary approaches for 3D structures can phenocopy the esophageal epithelium. Additionally, such cells form 3D structures when placed in Matrigel implants following transplantation under the kidney capsule. In the formation of the 3D structures, a requirement for Notch signaling is reinforced, although unlike the modulation of other pathways (BMP, WNT, and TGFβ), Notch signaling is apparently not needed for the specification of the anterior foregut endoderm into esophageal epithelium. By contrast, Trisno et al. undertook a complementary approach by first deriving foregut spheroids from hPSC-derived dorsal anterior foregut, rather than purifying putative progenitors. In doing so, they showed that Wnt and RA signaling regulate anterior foregut endodermal fate. In particular, they found that short-term RA activation promotes esophageal specification, and that inhibition of BMP signaling in foregut spheroids fosters a dorsal anterior foregut identity. The authors next showed that their hPSC-derived dorsal foregut spheroids formed esophageal 3D organoids with the expected features and markers of a non-keratinized squamous epithelium. Indeed, these organoids contain progenitor cells that can give rise to differentiating or transit-amplifying cells. The authors then applied their system to study the roles of Sox2 in esophageal development, finding that knockdown of Sox2 caused induction of Nkx2.1 and resultantly promoted an alternative airway fate. The importance of Sox2 was underscored through the generation of two mouse models that delete Sox2 in the foregut endoderm, which impaired esophageal development. Trisno et al. then showed that Sox2 may promote esophageal fate by inducing expression of Wnt antagonists, which could contribute to Wnt-dependent specification of dorsal versus ventral foregut identity. Both studies reveal common themes in the conversion of the anterior foregut endoderm to the specification of an esophageal epithelial fate. As such, these exciting results open up new perspectives and opportunities to investigate how hPSCs can be used to study not only normal human esophageal development and esophageal epithelial homeostasis, but also possibly conditions such as injurious states (erosive esophagitis), inflammatory states (eosinophilic esophagitis), esophageal intestinal metaplasia (Barrett’s Esophagus) (Jiang et al., 2017Jiang M. Li H. Zhang Y. Yang Y. Lu R. Liu K. Lin S. Lan X. Wang H. Wu H. et al.Transitional basal cells at the squamous-columnar junction generate Barrett’s oesophagus.Nature. 2017; 550: 529-533Crossref PubMed Scopus (127) Google Scholar) and esophageal cancer (squamous cell carcinoma and adenocarcinoma) (Dotto and Rustgi, 2016Dotto G.P. Rustgi A.K. Squamous cell cancers: a unified perspective on biology and genetics.Cancer Cell. 2016; 29: 622-637Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). 3D Modeling of Esophageal Development using Human PSC-Derived Basal Progenitors Reveals a Critical Role for Notch SignalingZhang et al.Cell Stem CellSeptember 20, 2018In BriefQue, Zhang, and colleagues established an efficient approach to differentiate human pluripotent stem cells (hPSCs) into esophageal progenitor cells (EPCs). Combined use of hPSC-derived EPCs and mouse genetic models demonstrates the important role of BMP and NOTCH signaling in promoting squamous differentiation of EPCs. Full-Text PDF Open ArchiveEsophageal Organoids from Human Pluripotent Stem Cells Delineate Sox2 Functions during Esophageal SpecificationTrisno et al.Cell Stem CellSeptember 20, 2018In BriefTrisno et al. have generated human esophageal organoids (HEOs) through the directed differentiation of pluripotent stem cells. HEOs contain esophageal progenitors and a differentiated stratified squamous epithelium. Using HEOs to model foregut development revealed that SOX2 regulates NKX2-1 through modulation of Wnt signaling. Full-Text PDF Open Archive" @default.
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- W2895524207 title "3D Human Esophageal Epithelium Steps Out from hPSCs" @default.
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