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Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells

Nature Biotechnology volume 29, pages 267–272 (2011)Cite this article

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Abstract

Directed differentiation of human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells captures in vivo developmental pathways for specifying lineages in vitro, thus avoiding perturbation of the genome with exogenous genetic material. Thus far, derivation of endodermal lineages has focused predominantly on hepatocytes, pancreatic endocrine cells and intestinal cells1,2,3,4,5. The ability to differentiate pluripotent cells into anterior foregut endoderm (AFE) derivatives would expand their utility for cell therapy and basic research to tissues important for immune function, such as the thymus; for metabolism, such as thyroid and parathyroid; and for respiratory function, such as trachea and lung. We find that dual inhibition of transforming growth factor (TGF)-β and bone morphogenic protein (BMP) signaling after specification of definitive endoderm from pluripotent cells results in a highly enriched AFE population that is competent to be patterned along dorsoventral and anteroposterior axes. These findings provide an approach for the generation of AFE derivatives.

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Figure 1: Induction of AFE markers in NOGGIN/SB-431542-treated definitive endoderm.
Figure 2: Immunofluorescence analysis of NOGGIN/SB-431542-treated definitive endoderm.
Figure 3: Functional characteristics of NOGGIN/SB-431542-induced AFE cells.
Figure 4: Induction of lung and pharyngeal pouch markers from ventral AFE generated in vitro.

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References

  1. D'Amour, K.A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006).

    Article  CAS  Google Scholar 

  2. Gouon-Evans, V. et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat. Biotechnol. 24, 1402–1411 (2006).

    Article  CAS  Google Scholar 

  3. Cai, J. et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45, 1229–1239 (2007).

    Article  CAS  Google Scholar 

  4. Murry, C.E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    Article  CAS  Google Scholar 

  5. Spence, J.R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2010).

    Article  CAS  Google Scholar 

  6. Yamanaka, S. A fresh look at iPS cells. Cell 137, 13–17 (2009).

    Article  CAS  Google Scholar 

  7. Gadue, P., Huber, T.L., Paddison, P.J. & Keller, G.M. Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc. Natl. Acad. Sci. USA 103, 16806–16811 (2006).

    Article  CAS  Google Scholar 

  8. Zorn, A.M. & Wells, J.M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009).

    Article  CAS  Google Scholar 

  9. Graham, A. Deconstructing the pharyngeal metamere. J. Exp. Zoolog. B Mol. Dev. Evol. 310, 336–344 (2008).

    Article  Google Scholar 

  10. Rodewald, H.R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355–388 (2008).

    Article  CAS  Google Scholar 

  11. Jenq, R.R. & van den Brink, M.R. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat. Rev. Cancer 10, 213–221 (2010).

    Article  CAS  Google Scholar 

  12. Lai, L. & Jin, J. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27, 3012–3020 (2009).

    CAS  PubMed  Google Scholar 

  13. Hidaka, K. et al. Differentiation of pharyngeal endoderm from mouse embryonic stem cell. Stem Cells Dev. 19, 1735–1743 (2010).

    Article  CAS  Google Scholar 

  14. Lin, R.Y., Kubo, A., Keller, G.M. & Davies, T.F. Committing embryonic stem cells to differentiate into thyrocyte-like cells in vitro. Endocrinology 144, 2644–2649 (2003).

    Article  CAS  Google Scholar 

  15. Bingham, E.L., Cheng, S.P., Woods Ignatoski, K.M. & Doherty, G.M. Differentiation of human embryonic stem cells to a parathyroid-like phenotype. Stem Cells Dev. 18, 1071–1080 (2009).

    Article  CAS  Google Scholar 

  16. Wang, D., Haviland, D.L., Burns, A.R., Zsigmond, E. & Wetsel, R.A. A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 104, 4449–4454 (2007).

    Article  CAS  Google Scholar 

  17. Yasunaga, M. et al. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat. Biotechnol. 23, 1542–1550 (2005).

    Article  CAS  Google Scholar 

  18. Sherwood, R.I., Chen, T.Y. & Melton, D.A. Transcriptional dynamics of endodermal organ formation. Dev. Dyn. 238, 29–42 (2009).

    Article  CAS  Google Scholar 

  19. Peters, H., Neubüser, A., Kratochwil, K. & Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12, 2735–2747 (1998).

    Article  CAS  Google Scholar 

  20. Li, Y. et al. Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev. 22, 3050–3063 (2008).

    Article  CAS  Google Scholar 

  21. Wood, H.B. & Episkopou, V. Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech. Dev. 86, 197–201 (1999).

    Article  CAS  Google Scholar 

  22. Weinstein, D.C. et al. The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell 78, 575–588 (1994).

    Article  CAS  Google Scholar 

  23. Chambers, S.M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280 (2009).

    Article  CAS  Google Scholar 

  24. Vitelli, F. et al. A genetic link between Tbx1 and fibroblast growth factor signaling. Development 129, 4605–4611 (2002).

    CAS  PubMed  Google Scholar 

  25. Bachiller, D. et al. The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development 130, 3567–3578 (2003).

    Article  CAS  Google Scholar 

  26. Morrisey, E.E. & Hogan, B.L. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev. Cell 18, 8–23 (2010).

    Article  CAS  Google Scholar 

  27. Tanaka, M., Schinke, M., Liao, H.S., Yamasaki, N. & Izumo, S. Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are required for development of the pharynx. Mol. Cell. Biol. 21, 4391–4398 (2001).

    Article  CAS  Google Scholar 

  28. Wallin, J. et al. Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23–30 (1996).

    CAS  PubMed  Google Scholar 

  29. Chen, F. et al. A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J. Clin. Invest. 120, 2040–2048 (2010).

    Article  CAS  Google Scholar 

  30. Moore-Scott, B.A. & Manley, N. Differential expression fo sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs. Dev. Biol. 278, 323–335 (2005).

    Article  CAS  Google Scholar 

  31. Lee, G.Y., Kenny, P.A., Lee, E.H. & Bissell, M.J. Three-dimensional culture models of normal and malignant breast epithelial cells. Nat. Methods 4, 359–365 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NYSTEM grant NO8G-422 to H.-W.S.

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Authors and Affiliations

  1. Department of Gene and Cell Medicine and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA

    Michael D Green, Antonia Chen, Sunita L d'Souza, Christoph Schaniel, Ihor R Lemischka, Valerie Gouon-Evans & Hans-Willem Snoeck

  2. Division of Stem Cell and Developmental Biology and McEwen Centre for Regenerative Medicine, Ontario Cancer Institute, Toronto, Ontario, Canada

    Maria-Cristina Nostro & Gordon Keller

Authors
  1. Michael D Green
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  2. Antonia Chen
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  9. Hans-Willem Snoeck
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Contributions

M.D.G. performed all experiments with assistance of A.C. M.-C.N., V.G.-E., S.L.S. and G.K. advised and assisted with induction of definitive endoderm. S.L.S., I.R.L. and C.S. generated and characterized the hiPS lines, respectively. M.D.G. and H.-W.S. designed the experiments and wrote the manuscript.

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Correspondence to Hans-Willem Snoeck.

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Competing interests

A patent application filed with the US Patent and Trade Office by M.G. and H.W.S. on the work reported in this article is pending.

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Supplementary Figs. 1–3 and Supplementary Table 1 (PDF 3430 kb)

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Green, M., Chen, A., Nostro, MC. et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat Biotechnol 29, 267–272 (2011). https://doi.org/10.1038/nbt.1788

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