Science China Life Sciences

, Volume 53, Issue 4, pp 497–503 | Cite as

Regulation of embryonic stem cell self-renewal and differentiation by TGF-β family signaling

Review

Abstract

Embryonic stem (ES) cells are characterized by their ability to indefinitely self-renew and potential to differentiate into all the cell lineages of the body. ES cells are considered to have potential applications in regenerative medicine. In particular, the emergence of an ES cell analogue — induced pluripotent stem (iPS) cells via somatic cell reprogramming by co-expressing a limited number of critical stemness-related transcriptional factors has solved the problem of obtaining patient-specific pluripotent cells, encouraging researchers to develop more specific and functional cell lineages from ES or iPS cells for broad therapeutic applications. ES cell fate choice is delicately controlled by a core transcriptional network, epigenetic modification profiles and complex signaling cascades both intrinsically and extrinsically. Of these signals, transforming growth factor β (TGF-β) family members, including TGF-β, bone morphogenetic protein (BMP), Activin and Nodal, have been reported to influence cell self-renewal and a broad spectrum of lineage differentiation in ES cells, in accordance with the key roles of TGF-β family signaling in early embryo development. In this review, the roles of TGF-β family signals in coordinating ES cell fate determination are summarized.

Keywords

embryonic stem cell TGF-β BMP Activin Nodal self-renewal differentiation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Evans M J, Kaufman M H. Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981, 292:154–156 10.1038/292154a0, 1:STN:280:DyaL3M3itV2qsg%3D%3D, 7242681PubMedCrossRefGoogle Scholar
  2. 2.
    Martin G R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA, 1981, 78:7634–7638 10.1073/pnas.78.12.7634, 1:STN:280:DyaL387ltV2htg%3D%3D, 6950406PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Thomson J A, Itskovitz-Eldor J, Shapiro S S, et al. Embryonic stem cell lines derived from human blastocysts. Science, 1998, 282:1145–1147 10.1126/science.282.5391.1145, 1:CAS:528:DyaK1cXntleisLg%3D, 9804556PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126:663–676 10.1016/j.cell.2006.07.024, 1:CAS:528:DC%2BD28Xpt1aktbs%3D, 16904174PubMedCrossRefGoogle Scholar
  5. 5.
    Chen L, Liu L. Current progress and prospects of induced pluripotent stem cells. Sci China C Life Sci, 2009, 52:622–636 10.1007/s11427-009-0092-6, 19641867PubMedCrossRefGoogle Scholar
  6. 6.
    Boyer L A, Mathur D, Jaenisch R. Molecular control of pluripotency. Curr Opin Genet Dev, 2006, 16:455–462 10.1016/j.gde.2006.08.009, 1:CAS:528:DC%2BD28Xps1Ogurg%3D, 16920351PubMedCrossRefGoogle Scholar
  7. 7.
    Niwa H. How is pluripotency determined and maintained? Development, 2007, 134:635–646 10.1242/dev.02787, 1:CAS:528:DC%2BD2sXjsVyrtLg%3D, 17215298PubMedCrossRefGoogle Scholar
  8. 8.
    Boiani M, Scholer H R. Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol, 2005, 6:872–884 10.1038/nrm1744, 1:CAS:528:DC%2BD2MXhtFKlsLzE, 16227977PubMedCrossRefGoogle Scholar
  9. 9.
    Datto M, Wang X F. The Smads: Transcriptional regulation and mouse models. Cytokine Growth Factor Rev, 2000, 11:37–48 10.1016/S1359-6101(99)00027-1, 1:CAS:528:DC%2BD3cXitlGjsr8%3D, 10708951PubMedCrossRefGoogle Scholar
  10. 10.
    Feng X H, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol, 2005, 21:659–693 10.1146/annurev.cellbio.21.022404.142018, 1:CAS:528:DC%2BD2MXhtlektbjM, 16212511PubMedCrossRefGoogle Scholar
  11. 11.
    Massague J, Chen Y G. Controlling TGF-beta signaling. Genes Dev, 2000, 14:627–644 1:CAS:528:DC%2BD3cXisVShu78%3D, 10733523PubMedGoogle Scholar
  12. 12.
    Smith A G. Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol, 2001, 17:435–462 10.1146/annurev.cellbio.17.1.435, 1:CAS:528:DC%2BD3MXos1Omsbo%3D, 11687496PubMedCrossRefGoogle Scholar
  13. 13.
    Niwa H, Burdon T, Chambers I, et al. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev, 1998, 12:2048–2060 10.1101/gad.12.13.2048, 1:CAS:528:DyaK1cXksFygtbk%3D, 9649508PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ying Q L, Nichols J, Chambers I, et al. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell, 2003, 115:281–292 10.1016/S0092-8674(03)00847-X, 1:CAS:528:DC%2BD3sXovFClu7c%3D, 14636556PubMedCrossRefGoogle Scholar
  15. 15.
    Qi X, Li T G, Hao J, et al. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA, 2004, 101:6027–6032 10.1073/pnas.0401367101, 1:CAS:528:DC%2BD2cXjsFKnsbo%3D, 15075392PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fei T, Xia K, Li Z, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res, 2010, 20:36–44 10.1101/gr.092114.109, 1:CAS:528:DC%2BC3cXls1OmtA%3D%3D, 19926752PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Xiao L, Yuan X, Sharkis S J. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells, 2006, 24:1476–1486 10.1634/stemcells.2005-0299, 1:CAS:528:DC%2BD28XhtFKlsbbM, 16456129PubMedCrossRefGoogle Scholar
  18. 18.
    James D, Levine A J, Besser D, et al. TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development, 2005, 132:1273–1282 10.1242/dev.01706, 1:CAS:528:DC%2BD2MXjsFentLs%3D, 15703277PubMedCrossRefGoogle Scholar
  19. 19.
    Wu Z, Zhang W, Chen G, et al. Combinatorial signals of activin/nodal and bone morphogenic protein regulate the early lineage segregation of human embryonic stem cells. J Biol Chem, 2008, 283:24991–25002 10.1074/jbc.M803893200, 1:CAS:528:DC%2BD1cXhtVGktbnF, 18596037PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Xu R H, Sampsell-Barron T L, Gu F, et al. NANOG is a direct target of TGFbeta/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell, 2008, 3:196–206 10.1016/j.stem.2008.07.001, 1:CAS:528:DC%2BD1cXhtVegtr%2FO, 18682241PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res, 2009, 19:103–115 10.1038/cr.2008.323, 1:CAS:528:DC%2BD1MXht1Ggsg%3D%3D, 19114993PubMedCrossRefGoogle Scholar
  22. 22.
    Liu A, Niswander L A. Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci, 2005, 6:945–954 10.1038/nrn1805, 1:CAS:528:DC%2BD2MXht12ntbvK, 16340955PubMedCrossRefGoogle Scholar
  23. 23.
    Finley M F, Devata S, Huettner J E. BMP-4 inhibits neural differentiation of murine embryonic stem cells. J Neurobiol, 1999, 40: 271–287 10.1002/(SICI)1097-4695(19990905)40:3<271::AID-NEU1>3.0.CO;2-C, 1:CAS:528:DyaK1MXlslKit7Y%3D, 10440729PubMedCrossRefGoogle Scholar
  24. 24.
    Ying Q L, Stavridis M, Griffiths D, et al. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol, 2003, 21:183–186 10.1038/nbt780, 1:CAS:528:DC%2BD3sXnsFWitQ%3D%3D, 12524553PubMedCrossRefGoogle Scholar
  25. 25.
    Vallier L, Reynolds D, Pedersen R A. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol, 2004, 275:403–421 10.1016/j.ydbio.2004.08.031, 1:CAS:528:DC%2BD2cXovVKltbg%3D, 15501227PubMedCrossRefGoogle Scholar
  26. 26.
    Chambers S M, Fasano C A, Papapetrou E P, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol, 2009, 27:275–280 10.1038/nbt.1529, 1:CAS:528:DC%2BD1MXisVOrtrc%3D, 19252484PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Aberdam D. Derivation of keratinocyte progenitor cells and skin formation from embryonic stem cells. Int J Dev Biol, 2004, 48: 203–206 10.1387/ijdb.15272386, 1:CAS:528:DC%2BD2cXmsVKlu7g%3D, 15272386PubMedCrossRefGoogle Scholar
  28. 28.
    Aberdam D, Gambaro K, Rostagno P, et al. Key role of p63 in BMP-4-induced epidermal commitment of embryonic stem cells. Cell Cycle, 2007, 6:291–294 1:CAS:528:DC%2BD2sXnvFygt7Y%3D, 17264680PubMedCrossRefGoogle Scholar
  29. 29.
    Loebel D A, Watson C M, De Young R A, et al. Lineage choice and differentiation in mouse embryos and embryonic stem cells. Dev Biol, 2003, 264:1–14 10.1016/S0012-1606(03)00390-7, 1:CAS:528:DC%2BD3sXovVeiu7w%3D, 14623228PubMedCrossRefGoogle Scholar
  30. 30.
    Olsen A L, Stachura D L, Weiss M J. Designer blood: Creating hematopoietic lineages from embryonic stem cells. Blood, 2006, 107:1265–1275 10.1182/blood-2005-09-3621, 1:CAS:528:DC%2BD28XhsFems7c%3D, 16254136PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Nakayama N, Lee J, Chiu L. Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro. Blood, 2000, 95:2275–2283 1:CAS:528:DC%2BD3cXitFeitrk%3D, 10733496PubMedGoogle Scholar
  32. 32.
    Park C, Afrikanova I, Chung Y S, et al. A hierarchical order of factors in the generation of FLK1- and SCL-expressing hematopoietic and endothelial progenitors from embryonic stem cells. Development, 2004, 131:2749–2762 10.1242/dev.01130, 1:CAS:528:DC%2BD2cXltlajt7s%3D, 15148304PubMedCrossRefGoogle Scholar
  33. 33.
    Lee D, Park C, Lee H, et al. ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell, 2008, 2:497–507 10.1016/j.stem.2008.03.008, 1:CAS:528:DC%2BD1cXmt1WrsL8%3D, 18462699PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lengerke C, Schmitt S, Bowman T V, et al. BMP and Wnt specify hematopoietic fate by activation of the Cdx-Hox pathway. Cell Stem Cell, 2008, 2:72–82 10.1016/j.stem.2007.10.022, 1:CAS:528:DC%2BD1cXhtFOlt7Y%3D, 18371423PubMedCrossRefGoogle Scholar
  35. 35.
    Singh A M, Terada N. Bypassing heterogeneity: The road to embryonic stem cell-derived cardiomyocyte specification. Trends Cardiovasc Med, 2007, 17:96–101 10.1016/j.tcm.2007.02.003, 1:CAS:528:DC%2BD2sXjvFGgtbc%3D, 17418371PubMedCrossRefGoogle Scholar
  36. 36.
    Parisi S, D’Andrea D, Lago C T, et al. Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. J Cell Biol, 2003, 163:303–314 10.1083/jcb.200303010, 1:CAS:528:DC%2BD3sXos1Sjt7s%3D, 14581455PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hao J, Daleo M A, Murphy C K, et al. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells. PLoS One, 2008, 3:e2904 10.1371/journal.pone.0002904, 18682835PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Yuasa S, Itabashi Y, Koshimizu U, et al. Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol, 2005, 23:607–611 10.1038/nbt1093, 1:CAS:528:DC%2BD2MXjvV2nur4%3D, 15867910PubMedCrossRefGoogle Scholar
  39. 39.
    Takei S, Ichikawa H, Johkura K, et al. Bone morphogenetic protein-4 promotes induction of cardiomyocytes from human embryonic stem cells in serum-based embryoid body development. Am J Physiol Heart Circ Physiol, 2009, 296:H1793–1803 10.1152/ajpheart.01288.2008, 1:CAS:528:DC%2BD1MXnsF2ltrk%3D, 19363129PubMedCrossRefGoogle Scholar
  40. 40.
    Buckingham M. Myogenic progenitor cells and skeletal myogenesis in vertebrates. Curr Opin Genet Dev, 2006, 16:525–532 10.1016/j.gde.2006.08.008, 1:CAS:528:DC%2BD28Xps1Ogu7k%3D, 16930987PubMedCrossRefGoogle Scholar
  41. 41.
    He L, Vichev K, Macharia R, et al. Activin A inhibits formation of skeletal muscle during chick development. Anat Embryol (Berl), 2005, 209:401–407 10.1007/s00429-005-0454-1, 1:CAS:528:DC%2BD2MXmtVSgu7c%3DCrossRefGoogle Scholar
  42. 42.
    Pisconti A, Brunelli S, Di Padova M, et al. Follistatin induction by nitric oxide through cyclic GMP: A tightly regulated signaling pathway that controls myoblast fusion. J Cell Biol, 2006, 172:233–244 10.1083/jcb.200507083, 1:CAS:528:DC%2BD28XntV2isw%3D%3D, 16401724PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Sakurai H, Inami Y, Tamamura Y, et al. Bidirectional induction toward paraxial mesodermal derivatives from mouse ES cells in chemically defined medium. Stem Cell Res, 2009, 3:157–169 10.1016/j.scr.2009.08.002, 1:CAS:528:DC%2BD1MXhsFGmsb%2FE, 19726261PubMedCrossRefGoogle Scholar
  44. 44.
    Schulz T J, Tseng Y H. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev, 2009, 20:523–531 10.1016/j.cytogfr.2009.10.019, 1:CAS:528:DC%2BD1MXhsV2msL%2FK, 19896888PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Taha M F, Valojerdi M R, Mowla S J. Effect of bone morphogenetic protein-4 (BMP-4) on adipocyte differentiation from mouse embryonic stem cells. Anat Histol Embryol, 2006, 35:271–278 10.1111/j.1439-0264.2006.00680.x, 1:STN:280:DC%2BD28vhsFakug%3D%3D, 16836593PubMedCrossRefGoogle Scholar
  46. 46.
    Heng B C, Cao T, Lee E H. Directing stem cell differentiation into the chondrogenic lineage in vitro. Stem Cells, 2004, 22:1152–1167 10.1634/stemcells.2004-0062, 15579636PubMedCrossRefGoogle Scholar
  47. 47.
    Heng B C, Cao T, Stanton L W, et al. Strategies for directing the differentiation of stem cells into the osteogenic lineage in vitro. J Bone Miner Res, 2004, 19:1379–1394 10.1359/JBMR.040714, 1:CAS:528:DC%2BD2cXotVGqtLw%3D, 15312238PubMedCrossRefGoogle Scholar
  48. 48.
    Kramer J, Hegert C, Guan K, et al. Embryonic stem cell-derived chondrogenic differentiation in vitro: Activation by BMP-2 and BMP-4. Mech Dev, 2000, 92:193–205 10.1016/S0925-4773(99)00339-1, 1:CAS:528:DC%2BD3cXhvV2ksLs%3D, 10727858PubMedCrossRefGoogle Scholar
  49. 49.
    Hajare M, Delphine C, Youssef H, et al. Osteogenic differentiation of ES cell-derived EBs mediated by embedded BMP-2 and TGF-beta-1 in a polyelectrolyte multilayer film. In: M. Firestone J S, N. Malmstadt eds. Mater Res Soc Symp Proc 950E. Warrendale, PA, 2007:0950-D0910-0904Google Scholar
  50. 50.
    Zaret K S, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science, 2008, 322:1490–1494 10.1126/science.1161431, 1:CAS:528:DC%2BD1cXhsVGltbzM, 19056973PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Zhang D, Jiang W, Shi Y, et al. Generation of pancreatic islet cells from human embryonic stem cells. Sci China C-Life Sci, 2009, 52:615–621 10.1007/s11427-009-0095-3, 19641866PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res, 2009, 19: 429–438 10.1038/cr.2009.28, 1:CAS:528:DC%2BD1MXktVSlsbw%3D, 19255591PubMedCrossRefGoogle Scholar
  53. 53.
    Gouon-Evans V, Boussemart L, Gadue P, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol, 2006, 24:1402–1411 10.1038/nbt1258, 1:CAS:528:DC%2BD28XhtFyqtLzO, 17086172PubMedCrossRefGoogle Scholar
  54. 54.
    Soto-Gutierrez A, Kobayashi N, Rivas-Carrillo J D, et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat Biotechnol, 2006, 24: 1412–1419 10.1038/nbt1257, 1:CAS:528:DC%2BD28XhtFyqtLzN, 17086173PubMedCrossRefGoogle Scholar
  55. 55.
    Erlebacher A, Price K A, Glimcher L H. Maintenance of mouse trophoblast stem cell proliferation by TGF-beta/activin. Dev Biol, 2004, 275:158–169 10.1016/j.ydbio.2004.07.032, 1:CAS:528:DC%2BD2cXot1Wku7Y%3D, 15464579PubMedCrossRefGoogle Scholar
  56. 56.
    Schulz L C, Ezashi T, Das P, et al. Human embryonic stem cells as models for trophoblast differentiation. Placenta, 2008, 29 Suppl A:S10–16 10.1016/j.placenta.2007.10.009CrossRefGoogle Scholar
  57. 57.
    Ichida J K, Blanchard J, Lam K, et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 2009, 5:491–503 10.1016/j.stem.2009.09.012, 1:CAS:528:DC%2BD1MXhsFKltLvE, 19818703PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Lin T, Ambasudhan R, Yuan X, et al. A chemical platform for improved induction of human iPSCs. Nat Methods, 2009, 6:805–808 10.1038/nmeth.1393, 1:CAS:528:DC%2BD1MXht1OgsrzE, 19838168PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Maherali N, Hochedlinger K. Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol, 2009, 19:1718–1723 10.1016/j.cub.2009.08.025, 1:CAS:528:DC%2BD1MXhtlCrsrvI, 19765992PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life SciencesTsinghua UniversityBeijingChina

Personalised recommendations