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Intestinal Mesenchymal Cells

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Abstract

The non–white blood cell mesenchymal elements of the intestinal lamina propria are the myofibroblasts, fibroblasts, pericytes, stromal stem cells, muscularis mucosae, and the smooth muscle of the villus core associated with the lymphatic lacteal. We review the functional anatomy of these mesenchymal cells, what is known about their origin in the embryo and their replacement in adults, their putative role in intestinal mucosal morphogenesis, and the intestinal stem cell niche, and we consider new information about myofibroblasts as nonprofessional immune cells. Although our knowledge of the function of mesenchymal cells in intestinal disease is rudimentary, we briefly consider here their roles in cancer and intestinal inflammation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Andoh A, Bamba S, Brittan M, et al.: Role of intestinal subepithelial myofibroblasts in inflammation and regenerative response in the gut. Pharmacol Ther 2007, 114:94–106. This comprehensive review of myofibroblast biology covers the cytokine/chemokine networks, cascades, and receptors expressed by intestinal myofibroblast. The focus on IL-22, IL-23, IL-17, and the proinflammatory cyokines as well as secretion of matrix modifying molecules such as the matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) indicate the potential role for these cells in inflamatory bowel disease pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  2. • Powell DW, Pinchuk IV, Saada JI, et al.: Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol 2011, in press. This review is an expanded and more detailed version covering many of the issues discussed briefly in this present Current Gastroenterology Reports article.

  3. •• Furuya S, Furuya K: Subepithelial fibroblasts in intestinal villi: roles in intercellular communication. Int Rev Cytol 2007, 264:165–223. This is an outstanding review of the anatomy and biology of intestinal myofibroblasts from an entirely different perspective than the information in this Current Gastroenterology Report. This review by the Furuyas deals with, among other aspects, the mechanosensitive properties of myofibroblasts and how they act as a gap junction and adherens junction-connected network, contracting in response to purinergic and endothelial agonists.

    Article  CAS  PubMed  Google Scholar 

  4. Adegboyega PA, Mifflin RC, DiMari JF, et al.: Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps. Arch Pathol Lab Med 2002, 126:829–836.

    PubMed  Google Scholar 

  5. Powell DW, Adegboyega PA, Di Mari JF, Mifflin RC: Epithelial cells and their neighbors I. Role of intestinal myofibroblasts in development, repair, and cancer. Am J Physiol Gastrointest Liver Physiol 2005, 289:G2–G7.

    Article  CAS  PubMed  Google Scholar 

  6. Bellini A, Mattoli S: The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibrosis. Lab Invest 2007, 87:858–870.

    Article  CAS  PubMed  Google Scholar 

  7. Brown SL, Riehl TE, Walker MR, et al.: Myd88-dependent positioning of PTGS2-expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest 2007, 117:258–269.

    Article  CAS  PubMed  Google Scholar 

  8. Ma B, von Wasielewski R, Lindenmaier W, Dittmar KE: Immmunohistochemical study of the blood and lymphatic vasculature and the innervation of mouse gut and gut-associated lymphoid tissue. Anat Histol Embryol 2007, 36:62–74.

    Article  CAS  PubMed  Google Scholar 

  9. Adegboyega PA, Ololade O, Saada J, et al.: Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas. Clin Cancer Res 2004, 10:5870–5879.

    Article  CAS  PubMed  Google Scholar 

  10. Madison BB, Braunstein K, Kuizon E, et al.: Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 2005, 132:279–289.

    Article  CAS  PubMed  Google Scholar 

  11. Rege TA, Hagood JS: Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J 2006, 20:1045–1054.

    Article  CAS  PubMed  Google Scholar 

  12. McLin VA, Henning SJ, Jamrich M: The role of the visceral mesoderm in the development of the gastrointestinal tract. Gastroenterology 2009, 136:2074–2091.

    Article  CAS  PubMed  Google Scholar 

  13. Joseph NM, Mukouyama YS, Mosher JT, et al.: Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to schwann cells. Development 2004, 131:5599–5612.

    Article  CAS  PubMed  Google Scholar 

  14. Muller SM, Stolt CC, Terszowski G, et al.: Neural crest origin of perivascular mesenchyme in the adult thymus. J Immunol 2008, 180:5344–5351.

    PubMed  Google Scholar 

  15. Wilm B, Ipenberg A, Hastie ND, et al.: The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature. Development 2005, 132:5317–5328.

    Article  CAS  PubMed  Google Scholar 

  16. Zeisberg M, Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009, 119:1429–1437.

    Article  CAS  PubMed  Google Scholar 

  17. Humphreys BD, Lin S-L, Kobayashi A, et al.: Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 2010, 176:85–97.

    Article  CAS  PubMed  Google Scholar 

  18. Taura K, Miura K, Iwaisako K, et al.: Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 2010, 51:1027–1036.

    Article  PubMed  Google Scholar 

  19. Rieder F, Brenmoehl J, Leeb S, et al.: Wound healing and fibrosis in intestinal disease. Gut 2007, 56:130–139.

    Article  CAS  PubMed  Google Scholar 

  20. Brittan M, Chance V, Elia G, et al.: A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology 2005, 128:1984–1995.

    Article  PubMed  Google Scholar 

  21. Uccelli A, Moretta L, Pistoia V: Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008, 8:726–736.

    Article  CAS  PubMed  Google Scholar 

  22. van den Brink GR: Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev 2007, 87:1343–1375.

    Article  PubMed  Google Scholar 

  23. Zacharias WJ, Li X, Madison BB, et al.: Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria. Gastroenterology 2010

  24. Kosinski C, Stange DE, Xu C, et al.: Indian hedgehog regulates intestinal stem cell fate through epithelial mesenchymal interactions during development. Gastroenterology 2010 (Epub ahead of print).

  25. Vignes S, Bellanger J: Primary intestinal lymphangiectasia (Waldmann’s disease). Orphanet J Rare Dis 2008, 3:5.

    Article  PubMed  Google Scholar 

  26. •• van der Flier LG, Clevers H: Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009, 71:241–260. This article provides a thorough review of intestinal stem cell biology and the importance of Wnt signaling. The authors discuss the numerous landmark findings that have recently come from the Clevers laboratory.

    Article  PubMed  Google Scholar 

  27. Miyazono K, Kamiya Y, Morikawa M: Bone morphogenetic protein receptors and signal transduction. J Biochem 2010, 147:35–51.

    Article  CAS  PubMed  Google Scholar 

  28. • Kosinski C, Li VS, Chan AS, et al.: Gene expression patterns of human colon tops and basal crypts and bmp antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A 2007, 104:15418–15423. This article, from the laboratory of Xin Chen, demonstrates the participation of both cryptal myofibroblasts and muscularis mucosae cells in establishment of the intestinal epithelial stem cell niche by elaboration of Bmp inhibitors within the cryptal region.

    Article  CAS  PubMed  Google Scholar 

  29. van Dop WA, Uhmann A, Wijgerde M, et al.: Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the hedgehog pathway. Gastroenterology 2009, 136:2195–2203 e2191–2197.

    Article  PubMed  Google Scholar 

  30. •• Egeblad M, Nakasone ES, Werb Z: Tumors as organs: complex tissues that interface with the entire organism. Developmental Cell 2010, 18:884–901. This article is a thorough recent review detailing important concepts relating to epithelial-stromal interactions during carcinogenesis.

    Article  CAS  PubMed  Google Scholar 

  31. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006, 6:392.

    Article  CAS  PubMed  Google Scholar 

  32. Orimo A, Gupta PB, Sgroi DC, et al.: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCl12 secretion. Cell 2005, 121:335–348.

    Article  CAS  PubMed  Google Scholar 

  33. Bhowmick NA, Chytil A, Plieth D, et al.: TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004, 303:848–851.

    Article  CAS  PubMed  Google Scholar 

  34. Shao J, Sheng GG, Mifflin RC, et al.: Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res 2006, 66:846–855.

    Article  CAS  PubMed  Google Scholar 

  35. Hardwick JC, Kodach LL, Offerhaus GJ, van den Brink GR: Bone morphogenetic protein signalling in colorectal cancer. Nat Rev Cancer 2008, 8:806–812.

    Article  CAS  PubMed  Google Scholar 

  36. Wang DH, Clemons NJ, Miyashita T, et al.: Aberrant epithelial mesenchymal hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology 2010, 138:1810–1822.

    Article  CAS  PubMed  Google Scholar 

  37. Otte JM, Rosenberg IM, Podolsky DK: Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 2003, 124:1866–1878.

    Article  CAS  PubMed  Google Scholar 

  38. Pang G, Couch L, Batey R, et al.: GM-CSF, IL-1, IL-1, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1 and TNF. Clin Exp Immunol 1994, 96:437–443.

    Article  CAS  PubMed  Google Scholar 

  39. Saada JI, Pinchuk IV, Barrera CA, et al.: Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa. J Immunol 2006, 177:5968–5979.

    CAS  PubMed  Google Scholar 

  40. • Jones S, Horwood N, Cope A, Dazzi F: The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol 2007, 179:2824–2831. This article is an excellent innovative research report that presents evidence that mature mesenchymal stromal cells play a tolerogenic function in T-cell homeostasis via suppression of the activation/proliferation of T cells. Further, the authors present evidence that this immunosupressive effect is a fundamental characteristic of all mesenchymal stromal cells.

    CAS  PubMed  Google Scholar 

  41. • Pinchuk IV, Saada JI, Beswick EJ, et al.: PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 2008, 135:1228–1237. This research paper develops further our recent finding pointing out that CD90 + mesenchymal stromal cells function as non professional antigen presenting cells that may act as suppressors of activated CD4 + T cell responses to acheivew homeostasis. The authors outline mechanisms involved in the cell contact mediated suppression of activated effector T cells.

    Article  CAS  PubMed  Google Scholar 

  42. Clark RA, Kupper TS: IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 2007, 109:194–202.

    Article  CAS  PubMed  Google Scholar 

  43. •• Flavell SJ, Hou TZ, Lax S, et al.: Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol 2008, 153(Suppl 1):S241–S246. This is an innovative review that further develops the concept proposed by Buckley et al. in 2001 suggesting the key role of stromal mesenchymal cells (i.e., fibroblasts) in the switch from acute to chronic inflammation and its application for the development of therapy against chronic inlammatory diseases.

    CAS  PubMed  Google Scholar 

  44. Pinchuk IV, Beswick EJ, Saada JI, et al.: Monocyte chemoattractant protein-1 production by intestinal myofibroblasts in response to staphylococcal enterotoxin A: relevance to staphylococcal enterotoxigenic disease. J Immunol 2007, 178:8097–8106.

    CAS  PubMed  Google Scholar 

  45. Rogler G, Gelbmann CM, Vogl D, et al.: Differential activation of cytokine secretion in primary human colonic fibroblast/myofibroblast cultures. Scand J Gastroenterol 2001, 36:389–398.

    Article  CAS  PubMed  Google Scholar 

  46. Wright MC, Issa R, Smart DE, et al.: Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 2001, 121:685–698.

    Article  CAS  PubMed  Google Scholar 

  47. Mei SH, Haitsma JJ, Dos Santos CC, et al.: Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010

  48. Lawrance IC, Maxwell L, Doe W: Altered response of intestinal mucosal fibroblasts to profibrogenic cytokines in inflammatory bowel disease. Inflamm Bowel Dis 2001, 7:226–236.

    Article  CAS  PubMed  Google Scholar 

  49. Okayasu I, Yoshida T, Mikami T, et al.: Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia: Significant alterations of NCAM+ or alpha-SMA+ subepithelial myofibroblasts and interstitial cells. Pathol Int 2009, 59:701–711.

    Article  CAS  PubMed  Google Scholar 

  50. Francoeur C, Bouatrouss Y, Seltana A, et al.: Degeneration of the pericryptal myofibroblast sheath by proinflammatory cytokines in inflammatory bowel diseases. Gastroenterology 2009, 136:268–277.

    Article  CAS  PubMed  Google Scholar 

  51. Powell DW, Mifflin RC, Valentich JD, et al.: Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 1999;277:C1–C9.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The research performed in the authors’ laboratories mentioned in this article was supported by grants from the National Institutes of Health, DK 55783 and CA 127229 (both to Dr. Powell), and an American Gastroenterological Association Scholars Award (Dr. Pinchuk).

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No potential conflict of interest relevant to this article was reported.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555-0764, USA

    I. V. Pinchuk, R. C. Mifflin, J. I. Saada & D. W. Powell

  2. Departments of Internal Medicine and Neuroscience and Cell Biology, 4.106 McCullough 0764, 301 University Boulevard, Galveston, TX, 77555-0764, USA

    D. W. Powell

Authors
  1. I. V. Pinchuk
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  2. R. C. Mifflin
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  3. J. I. Saada
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  4. D. W. Powell
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Correspondence to D. W. Powell.

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Pinchuk, I.V., Mifflin, R.C., Saada, J.I. et al. Intestinal Mesenchymal Cells. Curr Gastroenterol Rep 12, 310–318 (2010). https://doi.org/10.1007/s11894-010-0135-y

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  • DOI: https://doi.org/10.1007/s11894-010-0135-y

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