Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury

Abstract

Regeneration and homeostasis in the adult intestinal epithelium is driven by proliferative resident stem cells, whose functional properties during organismal development are largely unknown. Here, we show that human and mouse fetal intestine contains proliferative, immature progenitors, which can be expanded in vitro as Fetal Enterospheres (FEnS). A highly similar progenitor population can be established during intestinal differentiation of human induced pluripotent stem cells. Established cultures of mouse fetal intestinal progenitors express lower levels of Lgr5 than mature progenitors and propagate in the presence of the Wnt antagonist Dkk1, and new cultures can be induced to form mature intestinal organoids by exposure to Wnt3a. Following transplantation in a colonic injury model, FEnS contribute to regeneration of colonic epithelium by forming epithelial crypt-like structures expressing region-specific differentiation markers. This work provides insight into mechanisms underlying development of the mammalian intestine and points to future opportunities for patient-specific regeneration of the digestive tract.

References 26

1. 1.

   Barker N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003-1007.

   Not in our library10.1038/nature06196

2. 2.

   Barker N., van Oudenaarden A., Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell. 2012;11:452-460.

   Not in our library10.1016/j.stem.2012.09.009

3. 3.

   Brown S., Teo A., Pauklin S., Hannan N., Cho C.H.-H., Lim B., Vardy L., Dunn N.R., Trotter M., Pedersen R., Vallier L. Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells. 2011;29:1176-1185.

   Not in our library10.1002/stem.666

4. 4.

   de Lau W., Barker N., Low T.Y., Koo B.K., Li V.S., Teunissen H., Kujala P., Haegebarth A., Peters P.J., van de Wetering M. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476:293-297.

   Not in our library10.1038/nature10337

5. 5.

   Farin H.F., Van Es J.H., Clevers H. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology. 2012;143:1518-1529.

   Not in our library10.1053/j.gastro.2012.08.031

6. 6.

   Garcia M.I., Ghiani M., Lefort A., Libert F., Strollo S., Vassart G. LGR5 deficiency deregulates Wnt signaling and leads to precocious Paneth cell differentiation in the fetal intestine. Dev. Biol. 2009;331:58-67.

   Not in our library10.1016/j.ydbio.2009.04.020

7. 7.

   Gregorieff A., Pinto D., Begthel H., Destrée O., Kielman M., Clevers H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology. 2005;129:626-638.

   Not in our library10.1016/j.gastro.2005.06.007

8. 8.

   Hannan N.R.F., Fordham R.P., Moignard V., Jensen K.B., Vallier L. Generation of Multipotent Foregut Stem Cells from Human Pluripotent Stem Cells. Stem Cell Reports. 2013;1:293-306.

   Not in our library10.1016/j.stemcr.2013.09.003

9. 9.

   Jung P., Sato T., Merlos-Suárez A., Barriga F.M., Iglesias M., Rossell D., Auer H., Gallardo M., Blasco M.A., Sancho E. Isolation and in vitro expansion of human colonic stem cells. Nat. Med. 2011;17:1225-1227.

   Not in our library10.1038/nm.2470

10. 10.

    Koch S., Nava P., Addis C., Kim W., Denning T.L., Li L., Parkos C.A., Nusrat A. The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair. Gastroenterology. 2011;141:259-268.

    Not in our library10.1053/j.gastro.2011.03.043

11. 11.

    Korinek V., Barker N., Moerer P., van Donselaar E., Huls G., Peters P.J., Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 1998;19:379-383.

    Not in our library10.1038/1270

12. 12.

    Lin H.-T., Otsu M., Nakauchi H. Stem cell therapy: an exercise in patience and prudence. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013;368:20110334.

    Not in our library10.1098/rstb.2011.0334

13. 13.

    Lustig B., Jerchow B., Sachs M., Weiler S., Pietsch T., Karsten U., van de Wetering M., Clevers H., Schlag P.M., Birchmeier W., Behrens J. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol. Cell. Biol. 2002;22:1184-1193.

    Not in our library10.1128/mcb.22.4.1184-1193.2002

14. 14.

    Meyer J.S., Shearer R.L., Capowski E.E., Wright L.S., Wallace K.A., McMillan E.L., Zhang S.-C., Gamm D.M. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc. Natl. Acad. Sci. USA. 2009;106:16698-16703.

    Not in our library10.1073/pnas.0905245106

15. 15.

    Montgomery R.K., Mulberg A.E., Grand R.J. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology. 1999;116:702-731.

    Not in our library10.1016/s0016-5085(99)70193-9

16. 16.

    Nicholas C.R., Chen J., Tang Y., Southwell D.G., Chalmers N., Vogt D., Arnold C.M., Chen Y.-J.J., Stanley E.G., Elefanty A.G. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell. 2013;12:573-586.

    Not in our library10.1016/j.stem.2013.04.005

17. 17.

    Okabe M., Ikawa M., Kominami K., Nakanishi T., Nishimune Y. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 1997;407:313-319.

    Not in our library10.1016/s0014-5793(97)00313-x

18. 18.

    Rashid S.T., Corbineau S., Hannan N., Marciniak S.J., Miranda E., Alexander G., Huang-Doran I., Griffin J., Ahrlund-Richter L., Skepper J. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 2010;120:3127-3136.

    Not in our library10.1172/jci43122

19. 19.

    Sato T., Vries R.G., Snippert H.J., van de Wetering M., Barker N., Stange D.E., van Es J.H., Abo A., Kujala P., Peters P.J., Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262-265.

    Not in our library10.1038/nature07935

20. 20.

    Sato T., Stange D.E., Ferrante M., Vries R.G.J., Van Es J.H., Van den Brink S., Van Houdt W.J., Pronk A., Van Gorp J., Siersema P.D., Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762-1772.

    Not in our library10.1053/j.gastro.2011.07.050

21. 21.

    Sato T., van Es J.H., Snippert H.J., Stange D.E., Vries R.G., van den Born M., Barker N., Shroyer N.F., van de Wetering M., Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469:415-418.

    Not in our library10.1038/nature09637

22. 22.

    Spence J.R., Lauf R., Shroyer N.F. Vertebrate intestinal endoderm development. Dev. Dyn. 2011;240:501-520.

    Not in our library10.1002/dvdy.22540

23. 23.

    Spence J.R., Mayhew C.N., Rankin S.A., Kuhar M.F., Vallance J.E., Tolle K., Hoskins E.E., Kalinichenko V.V., Wells S.I., Zorn A.M. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470:105-109.

    Not in our library10.1038/nature09691

24. 24.

    Wong V.W.Y., Stange D.E., Page M.E., Buczacki S., Wabik A., Itami S., van de Wetering M., Poulsom R., Wright N.A., Trotter M.W.B. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 2012;14:401-408.

    Not in our library10.1038/ncb2464

25. 25.

    Yui S., Nakamura T., Sato T., Nemoto Y., Mizutani T., Zheng X., Ichinose S., Nagaishi T., Okamoto R., Tsuchiya K. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 2012;18:618-623.

    Not in our library10.1038/nm.2695

26. 26.

    Zorn A.M., Wells J.M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 2009;25:221-251.

    Not in our library10.1146/annurev.cellbio.042308.113344

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