Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stem cells in gastroenterology and hepatology

Nature Reviews Gastroenterology & Hepatology volume 6, pages 724–737 (2009)Cite this article

This article has been updated

Abstract

Cellular and tissue regeneration in the gastrointestinal tract and liver depends on stem cells with properties of longevity, self-renewal and multipotency. Progress in stem cell research and the identification of potential esophageal, gastric, intestinal, colonic, hepatic and pancreatic stem cells provides hope for the use of stem cells in regenerative medicine and treatments for disease. Embryonic stem cells and induced pluripotent stem cells have the potential to give rise to any cell type in the human body, but their therapeutic application remains challenging. The use of adult or tissue-restricted stem cells is emerging as another possible approach for the treatment of gastrointestinal diseases. The same self-renewal properties that allow stem cells to remain immortal and generate any tissue can occasionally make their proliferation difficult to control and make them susceptible to malignant transformation. This Review provides an overview of the different types of stem cell, focusing on tissue-restricted adult stem cells in the fields of gastroenterology and hepatology and summarizing the potential benefits and risks of using stems cells to treat gastroenterological and liver disorders.

Key Points

  • Cellular regeneration depends on stem cells, which are primitive and relatively unspecialized cells present in fetal and adult tissues that have properties of longevity, self-renewal and multipotency

  • Stem cells can be classified as embryonic or adult, and within the gastrointestinal tract they can be further subdivided into esophageal, gastric, intestinal, colonic, hepatic and pancreatic stem cells

  • Tissue-restricted stem cells are difficult to identify and are distinguished from epithelial cells by their ability to proliferate and self-renew; they reside within a 'niche' that provides an optimal microenvironment for growth

  • The same self-renewal properties that allow stem cells to remain immortal and generate thousands of progeny can occasionally make their proliferation difficult to control and thus susceptible to malignant transformation

  • In the fields of gastroenterology and hepatology, stem cells could be used to restore tissue function in patients with failure of the liver, small intestine or pancreas

  • In addition to embryonic stem cells, the recent discovery of induced pluripotent stem cells has led to a potential alternative strategy for the development of patient-specific cell therapy

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic illustration of the potency and differentiation status of the different stem cells and progenitor cells or differentiated tissue cells that are relevant to gastroenterology.
Figure 2: Schematic illustration of the location of putative intestinal stem cells and/or progenitor cells and their markers in the crypt of the intestine.
Figure 3: Schematic illustration of the different location and structural organization of stem cells in the gut.

Similar content being viewed by others

Change history

  • 11 November 2009

    In the version of this article initially published online, the order of some of the references cited in the text, tables and the reference list was incorrect. The error has been corrected for all versions of the article.

References

  1. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  PubMed  Google Scholar 

  2. Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).

    CAS  PubMed  Google Scholar 

  3. Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

    CAS  PubMed  Google Scholar 

  4. Chuong, C. M. & Widelitz, R. B. The river of stem cells. Cell Stem Cell 4, 100–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Leblond, C. P., Stevens, C. E. & Bogoroch, R. Histological localization of newly-formed desoxyribonucleic acid. Science 108, 531–533 (1948).

    CAS  PubMed  Google Scholar 

  6. Daley, G. Q. & Scadden, D. T. Prospects for stem cell-based therapy. Cell 132, 544–548 (2008).

    CAS  PubMed  Google Scholar 

  7. Stappenbeck, T. S. & Miyoshi, H. The role of stromal stem cells in tissue regeneration and wound repair. Science 324, 1666–1669 (2009).

    CAS  PubMed  Google Scholar 

  8. Brittan, M., Alison, M. R., Schier, S. & Wright, N. A. Bone marrow stem cell-mediated regeneration in IBD: where do we go from here? Gastroenterology 132, 1171–1173 (2007).

    PubMed  Google Scholar 

  9. Hamburger, A. W. & Salmon, S. E. Primary bioassay of human tumor stem cells. Science 197, 461–463 (1977).

    CAS  PubMed  Google Scholar 

  10. Rosen, J. M. & Jordan, C. T. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988).

    CAS  PubMed  Google Scholar 

  12. Stemple, D. L. & Anderson, D. J. Lineage diversification of the neural crest: in vitro investigations. Dev. Biol. 159, 12–23 (1993).

    CAS  PubMed  Google Scholar 

  13. Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  PubMed  Google Scholar 

  15. Booth, D., Haley, J. D., Bruskin, A. M. & Potten, C. S. Transforming growth factor-B3 protects murine small intestinal crypt stem cells and animal survival after irradiation, possibly by reducing stem-cell cycling. Int. J. Cancer 86, 53–59 (2000).

    CAS  PubMed  Google Scholar 

  16. Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105, 1493–1499 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Brittan, M. et al. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 50, 752–757 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yen, T. H. & Wright, N. A. The gastrointestinal tract stem cell niche. Stem Cell Rev. 2, 203–212 (2006).

    CAS  PubMed  Google Scholar 

  20. Barker, N., van de Wetering, M. & Clevers, H. The intestinal stem cell. Genes Dev. 22, 1856–1864 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 14, 262–265 (2009).

    Google Scholar 

  22. Fuchs, E. The tortoise and the hair: slow-cycling cells in the stem cell race. Cell 137, 811–819 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bjerknes, M. & Cheng, H. The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. Am. J. Anat. 160, 77–91 (1981).

    CAS  PubMed  Google Scholar 

  24. Potten, C. S., Kovacs, L. & Hamilton, E. Continuous labelling studies on mouse skin and intestine. Cell Tissue Kinet. 7, 271–283 (1974).

    CAS  PubMed  Google Scholar 

  25. Barker, N. & Clevers, H. Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology 133, 1755–1760 (2007).

    CAS  PubMed  Google Scholar 

  26. Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009).

    CAS  PubMed  Google Scholar 

  27. Snippert, H. J. et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 136, 2051–2054 (2009).

    Google Scholar 

  28. van der Flier, L. G., Haegebarth, A., Stange, D. E., van de Wetering, M. & Clevers, H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).

    PubMed  Google Scholar 

  29. Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kayahara, T. et al. Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett. 535, 131–135 (2003).

    CAS  PubMed  Google Scholar 

  31. Murata, H. et al. Helicobacter pylori infection induces candidate stem cell marker Musashi-1 in the human gastric epithelium. Dig. Dis. Sci. 53, 363–369 (2008).

    CAS  PubMed  Google Scholar 

  32. Gregorieff, A. et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).

    CAS  PubMed  Google Scholar 

  33. He, X. C. et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat. Genet. 39, 189–198 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat. Genet. 36, 1117–1121 (2004).

    CAS  PubMed  Google Scholar 

  35. Giannakis, M. et al. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J. Biol. Chem. 281, 11292–11300 (2006).

    CAS  PubMed  Google Scholar 

  36. May, R. et al. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26, 630–637 (2008).

    PubMed  Google Scholar 

  37. Jin, G. et al. Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J. Clin. Invest. 119, 2691–2701 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318–323 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Campbell, F. et al. Post-irradiation somatic mutation and clonal stabilisation time in the human colon. Gut 39, 569–573 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fellous, T. G. et al. A methodological approach to tracing cell lineage in human epithelial tissues. Stem Cells 27, 1410–1420 (2009).

    CAS  PubMed  Google Scholar 

  41. Gutierrez-Gonzalez, L. et al. Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations. J. Pathol. 217, 489–496 (2009).

    CAS  PubMed  Google Scholar 

  42. Scoville, D. H., Sato, T., He, X. C. & Li, L. Current view: intestinal stem cells and signaling. Gastroenterology 134, 849–864 (2008).

    CAS  PubMed  Google Scholar 

  43. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    CAS  PubMed  Google Scholar 

  44. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).

    CAS  PubMed  Google Scholar 

  45. Potten, C. S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002).

    CAS  PubMed  Google Scholar 

  46. Qiao, X. T. et al. Prospective identification of a multilineage progenitor in murine stomach epithelium. Gastroenterology 133, 1989–1998 (2007).

    CAS  PubMed  Google Scholar 

  47. McDonald, S. A. et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134, 500–510 (2008).

    CAS  PubMed  Google Scholar 

  48. Leblond, C. P. Classification of cell populations on the basis of their proliferative behavior. Natl Cancer Inst. Monogr. 14, 119–150 (1964).

    CAS  PubMed  Google Scholar 

  49. Seery, J. P. & Watt, F. M. Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr. Biol. 10, 1447–1450 (2000).

    CAS  PubMed  Google Scholar 

  50. Lu, B., Roegiers, F., Jan, L. Y. & Jan, Y. N. Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature 409, 522–525 (2001).

    CAS  PubMed  Google Scholar 

  51. Lavker, R. M. & Sun, T. T. Epidermal stem cells: properties, markers, and location. Proc. Natl Acad. Sci. USA 97, 13473–13475 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jones, P. H. & Watt, F. M. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73, 713–724 (1993).

    CAS  PubMed  Google Scholar 

  53. Kalabis, J. et al. A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J. Clin. Invest. 118, 3860–3869 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Fausto, N. & Campbell, J. S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120, 117–130 (2003).

    CAS  PubMed  Google Scholar 

  55. Zaret, K. S. & Grompe, M. Generation and regeneration of cells of the liver and pancreas. Science 322, 1490–1494 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fellous, T. G. et al. Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49, 1655–1663 (2009).

    CAS  PubMed  Google Scholar 

  57. Rountree, C. B. et al. A CD133-expressing murine liver oval cell population with bilineage potential. Stem Cells 25, 2419–2429 (2007).

    CAS  PubMed  Google Scholar 

  58. Sackett, S. D. et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology 49, 920–929 (2009).

    CAS  PubMed  Google Scholar 

  59. Slack, J. M. Origin of stem cells in organogenesis. Science 322, 1498–1501 (2008).

    CAS  PubMed  Google Scholar 

  60. Manfroid, I. et al. Reciprocal endoderm-mesoderm interactions mediated by fgf24 and fgf10 govern pancreas development. Development 134, 4011–4021 (2007).

    CAS  PubMed  Google Scholar 

  61. Jung, J., Zheng, M., Goldfarb, M. & Zaret, K. S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284, 1998–2003 (1999).

    CAS  PubMed  Google Scholar 

  62. Suzuki, A., Sekiya, S., Buscher, D., Izpisua Belmonte, J. C. & Taniguchi, H. Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development 135, 1589–1595 (2008).

    CAS  PubMed  Google Scholar 

  63. McLin, V. A., Rankin, S. A. & Zorn, A. M. Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134, 2207–2217 (2007).

    CAS  PubMed  Google Scholar 

  64. Ober, E. A., Verkade, H., Field, H. A. & Stainier, D. Y. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442, 688–691 (2006).

    CAS  PubMed  Google Scholar 

  65. Dorrell, C. et al. Surface markers for the murine oval cell response. Hepatology 48, 1282–1291 (2008).

    CAS  PubMed  Google Scholar 

  66. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2002).

    CAS  PubMed  Google Scholar 

  67. Nishio, J. et al. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 311, 1775–1778 (2006).

    CAS  PubMed  Google Scholar 

  68. Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004).

    CAS  PubMed  Google Scholar 

  69. Stanger, B. Z., Tanaka, A. J. & Melton, D. A. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445, 886–891 (2007).

    CAS  PubMed  Google Scholar 

  70. Xu, X. et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197–207 (2008).

    CAS  PubMed  Google Scholar 

  71. Sangiorgi, E. & Capecchi, M. R. Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. Proc. Natl Acad. Sci. USA 106, 7101–7106 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sell, S. & Pierce, G. B. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab. Invest. 70, 6–22 (1994).

    CAS  PubMed  Google Scholar 

  73. Pierce, G. B. Neoplastic stem cells. Adv. Pathobiol. 6, 141–152 (1977).

    Google Scholar 

  74. Lobo, N. A., Shimono, Y., Qian, D. & Clarke, M. F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23, 675–699 (2007).

    CAS  PubMed  Google Scholar 

  75. Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L. & Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007).

    CAS  PubMed  Google Scholar 

  76. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    CAS  PubMed  Google Scholar 

  77. Takaishi, S. et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27, 1006–1020 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang, Z. F. et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47, 919–928 (2008).

    CAS  PubMed  Google Scholar 

  81. Takaishi, S., Okumura, T. & Wang, T. C. Gastric cancer stem cells. J. Clin. Oncol. 26, 2876–2882 (2008).

    PubMed  Google Scholar 

  82. Weigmann, A., Corbeil, D., Hellwig, A. & Huttner, W. B. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc. Natl Acad. Sci. USA 94, 12425–12430 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    CAS  PubMed  Google Scholar 

  84. Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).

    CAS  PubMed  Google Scholar 

  85. O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    CAS  PubMed  Google Scholar 

  86. Shmelkov, S. V. et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J. Clin. Invest. 118, 2111–2120 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ma, S. et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542–2556 (2007).

    CAS  PubMed  Google Scholar 

  89. Mishra, L. et al. Liver stem cells and hepatocellular carcinoma. Hepatology 49, 318–329 (2009).

    PubMed  Google Scholar 

  90. Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

    CAS  PubMed  Google Scholar 

  91. Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Mueller, M. T. et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 137, 1102–1113 (2009).

    CAS  PubMed  Google Scholar 

  94. Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).

    CAS  PubMed  Google Scholar 

  95. Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).

    CAS  PubMed  Google Scholar 

  96. LaBarge, M. A. & Blau, H. M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589–601 (2002).

    CAS  PubMed  Google Scholar 

  97. Houghton, J. et al. Gastric cancer originating from bone marrow-derived cells. Science 306, 1568–1571 (2004).

    CAS  PubMed  Google Scholar 

  98. Nygren, J. M. et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat. Cell Biol. 10, 584–592 (2008).

    CAS  PubMed  Google Scholar 

  99. Johansson, C. B. et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat. Cell Biol. 10, 575–583 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Avital, I. et al. Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. Stem Cells 25, 2903–2909 (2007).

    PubMed  Google Scholar 

  101. Janin, A. et al. Donor-derived oral squamous cell carcinoma after allogeneic bone marrow transplantation. Blood 113, 1834–1840 (2009).

    CAS  PubMed  Google Scholar 

  102. Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Orimo, A. & Weinberg, R. A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5, 1597–1601 (2006).

    CAS  PubMed  Google Scholar 

  104. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    CAS  PubMed  Google Scholar 

  105. Basma, H. et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 136, 990–999 (2009).

    CAS  PubMed  Google Scholar 

  106. Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2007).

    CAS  PubMed  Google Scholar 

  107. Metzger, M., Caldwell, C., Barlow, A. J., Burns, A. J. & Thapar, N. Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 136, 2214–2225 e1–3 (2009).

    CAS  PubMed  Google Scholar 

  108. Piscaglia, A. C., Shupe, T. D., Oh, S. H., Gasbarrini, A. & Petersen, B. E. Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology 133, 619–631 (2007).

    CAS  PubMed  Google Scholar 

  109. Gehling, U. M. et al. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J. Hepatol. 43, 845–853 (2005).

    CAS  PubMed  Google Scholar 

  110. am Esch, J. S. 2nd et al. Portal application of autologous CD133+ bone marrow cells to the liver: a novel concept to support hepatic regeneration. Stem Cells 23, 463–470 (2005).

    PubMed  Google Scholar 

  111. Terai, S. et al. Improved liver function in liver cirrhosis patients after autologous bone marrow cell infusion therapy. Stem Cells 24, 2292–2298 (2006).

    CAS  PubMed  Google Scholar 

  112. Kuo, T. K. et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 134, 2111–2121, e1–3 (2008).

    PubMed  Google Scholar 

  113. Khalil, P. N. et al. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 132, 944–954 (2007).

    PubMed  Google Scholar 

  114. Gonzalez, M. A., Gonzalez-Rey, E., Rico, L., Buscher, D. & Delgado, M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 136, 978–989 (2009).

    CAS  PubMed  Google Scholar 

  115. Rossant, J. Stem cells and early lineage development. Cell 132, 527–531 (2008).

    CAS  PubMed  Google Scholar 

  116. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  117. Smith, A. G. et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336, 688–690 (1988).

    CAS  PubMed  Google Scholar 

  118. Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J. & Campbell, K. H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).

    CAS  PubMed  Google Scholar 

  119. Hochedlinger, K. & Jaenisch, R. Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. N. Engl. J. Med. 349, 275–286 (2003).

    CAS  PubMed  Google Scholar 

  120. Nishikawa, S., Goldstein, R. A. & Nierras, C. R. The promise of human induced pluripotent stem cells for research and therapy. Nat. Rev. Mol. Cell Biol. 9, 725–729 (2008).

    CAS  PubMed  Google Scholar 

  121. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  122. Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).

    CAS  PubMed  Google Scholar 

  123. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).

    CAS  PubMed  Google Scholar 

  125. Kaji, K. et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771–775 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Markoulaki, S. et al. Transgenic mice with defined combinations of drug-inducible reprogramming factors. Nat. Biotechnol. 27, 169–171 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kim, J. B. et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646–650 (2008).

    CAS  PubMed  Google Scholar 

  129. Kim, J. B. et al. Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411–419 (2009).

    CAS  PubMed  Google Scholar 

  130. Shao, L. et al. Generation of iPS cells using defined factors linked via the self-cleaving 2A sequences in a single open reading frame. Cell Res. 19, 296–306 (2009).

    CAS  PubMed  Google Scholar 

  131. Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736 (2008).

    CAS  PubMed  Google Scholar 

  132. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  133. Covas, D. T. et al. Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp. Hematol. 36, 642–654 (2008).

    CAS  PubMed  Google Scholar 

  134. Okumura, T. et al. Identification of a bone marrow-derived mesenchymal progenitor cell subset that can contribute to the gastric epithelium. Lab. Invest. doi:10.1038/labinvest.2009.88

    PubMed  Google Scholar 

  135. Lee, K. D. et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40, 1275–1284 (2004).

    CAS  PubMed  Google Scholar 

  136. Ortiz, L. A. et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc. Natl Acad. Sci. USA 100, 8407–8411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Arnhold, S. et al. Adenovirally transduced bone marrow stromal cells differentiate into pigment epithelial cells and induce rescue effects in RCS rats. Invest. Ophthalmol. Vis. Sci. 47, 4121–4129 (2006).

    PubMed  Google Scholar 

  138. Kopen, G. C., Prockop, D. J. & Phinney, D. G. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc. Natl Acad. Sci. USA 96, 10711–10716 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Phinney, D. G. & Prockop, D. J. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 25, 2896–2902 (2007).

    PubMed  Google Scholar 

  140. Prockop, D. J. 'Stemness' does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin. Pharmacol. Ther. 82, 241–243 (2007).

    CAS  PubMed  Google Scholar 

  141. Karlsson, H. et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 112, 532–541 (2008).

    CAS  PubMed  Google Scholar 

  142. Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).

    CAS  PubMed  Google Scholar 

  143. Wang, S. W. et al. Bone marrow derived Lin-Cd44hisca1-Ckit+CD34- can give rise to mesenchymal stem cells and delay progression to dysplasia in a murine Helicobacter model of gastric cancer. Gastroenterology 136 (Suppl. 1), 58 (2009).

    Google Scholar 

Download references

Acknowledgements

T. C. Wang is supported by National Institutes of Health grants 1U54CA126513, RO1CA093405 and R01CA120979. M. Quante is supported by a grant from the Mildred-Scheel-Stiftung, Deutsche Krebshilfe, Germany.

Author information

Authors and Affiliations

  1. Division of Digestive and Liver Diseases, Columbia University Medical Center, Irving Cancer Research Center, New York, NY, USA

    Michael Quante & Timothy C. Wang

Authors
  1. Michael Quante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy C. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy C. Wang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quante, M., Wang, T. Stem cells in gastroenterology and hepatology. Nat Rev Gastroenterol Hepatol 6, 724–737 (2009). https://doi.org/10.1038/nrgastro.2009.195

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2009.195

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing