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Current Transplantation Reports

, Volume 6, Issue 2, pp 134–145 | Cite as

Mesenchymal Stem Cells to Treat Digestive System Disorders: Progress Made and Future Directions

  • Barbara Romano
  • Ana Lleo
  • Emanuela Sala
  • Giovanna D’Amico
  • Domenica Ida Marino
  • Rachele Ciccocioppo
  • Stefania VetranoEmail author
Cellular Transplants (G Orlando, Section Editor)
  • 27 Downloads
Part of the following topical collections:
  1. Topical Collection on Cellular Transplants

Abstract

Purpose of Review

The purpose of this review is to summarize the results from clinical trials that evoked promise and discouragement for the use of mesenchymal stem cells (MSCs) to treat digestive system disorders.

Recent Findings

Adult MSCs are defined as a non-homogeneous population of pluripotent progenitor cells, which can be isolated and expanded in vitro from different tissues. The differentiation capacity of MSC along mesenchymal lineages and their immunomodulatory properties have been considered a new therapeutic approach for intestinal disorders. A dysregulated immune response is the cause and sustainment of these disorders, as they are characterized by progressive tissue damage with no available curative treatment.

Up to now, 130 clinical trials on MSC-based therapy are registered to treat conditions affecting the digestive system.

Summary

The results from completed or underway clinical studies are encouraging, showing both benefit for those digestive disorders refractory to any conventional therapy and progression toward end-stage liver disease. However, the absence of large, robust controlled, and randomized clinical trials to assess MSC clinical efficacy limits MSC-based therapy translation to bedside reality to completely cure digestive disorders.

Keywords

graft-versus-host disease Inflammatory bowel disease Liver disorders Mesenchymal stem cells Perianal fistula Tissue regeneration 

Notes

Funding Information

The manuscript was supported by a grant from Ministero della Salute (GR -2009 Convenzione 76) to SV; My First AIRC Grant (MFAG 2015-17795) to SV.

Compliance with Ethical Standards

Conflict of Interest

Rachele Ciccocioppo received a consulting (honorary) fee by Takeda Pharmaceutical Company Limited (USA). Ana Lleo has served as a speaker for Abbvie, BMS, Gilead, and Intercept. Barbara Romano, Emanuela Sala, Giovanna D’Amico, Domenica Ida Marino and Stefania Vetrano have no conflicts of interest to declare.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276(5309):71–4.Google Scholar
  2. 2.
    Le Blanc K, Samuelsson H, Gustafsson B, Remberger M, Sundberg B, Arvidson J, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 2007;21(8):1733–8.  https://doi.org/10.1038/sj.leu.2404777.Google Scholar
  3. 3.
    Manieri NA, Stappenbeck TS. Mesenchymal stem cell therapy of intestinal disease: are their effects systemic or localized? Curr Opin Gastroenterol. 2011;27(2):119–24.  https://doi.org/10.1097/MOG.0b013e3283423f20.Google Scholar
  4. 4.
    Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976;4(5):267–74.Google Scholar
  5. 5.
    Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, Prockop DJ. Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells. 2002;20(6):530–41.  https://doi.org/10.1634/stemcells.20-6-530.Google Scholar
  6. 6.
    Castro-Malaspina H, Gay RE, Resnick G, Kapoor N, Meyers P, Chiarieri D, et al. Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood. 1980;56(2):289–301.Google Scholar
  7. 7.
    Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–5.  https://doi.org/10.1080/14653240500319234.Google Scholar
  8. 8.
    Haynesworth SE, Baber MA, Caplan AI. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone. 1992;13(1):69–80.Google Scholar
  9. 9.
    Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31(10):890–6.Google Scholar
  10. 10.
    Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone. 1992;13(1):81–8.Google Scholar
  11. 11.
    Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, et al. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res. 2000;2(6):477–88.  https://doi.org/10.1186/ar130.Google Scholar
  12. 12.
    Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(1):235–42.Google Scholar
  13. 13.
    Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells. 2005;23(2):220–9.  https://doi.org/10.1634/stemcells.2004-0166.Google Scholar
  14. 14.
    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95.  https://doi.org/10.1091/mbc.e02-02-0105.Google Scholar
  15. 15.
    In 't Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R, et al. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 2003;102(4):1548–9.  https://doi.org/10.1182/blood-2003-04-1291.Google Scholar
  16. 16.
    De Bari C, Dell'Accio F, Vandenabeele F, Vermeesch JR, Raymackers JM, Luyten FP. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol. 2003;160(6):909–18.  https://doi.org/10.1083/jcb.200212064.Google Scholar
  17. 17.
    Jones EA, English A, Henshaw K, Kinsey SE, Markham AF, Emery P, et al. Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum. 2004;50(3):817–27.  https://doi.org/10.1002/art.20203.Google Scholar
  18. 18.
    Nakahara H, Dennis JE, Bruder SP, Haynesworth SE, Lennon DP, Caplan AI. In vitro differentiation of bone and hypertrophic cartilage from periosteal-derived cells. Exp Cell Res. 1991;195(2):492–503.Google Scholar
  19. 19.
    Dowthwaite GP, Bishop JC, Redman SN, Khan IM, Rooney P, Evans DJ, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004;117(Pt 6):889–97.  https://doi.org/10.1242/jcs.00912.Google Scholar
  20. 20.
    Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood. 2001;98(8):2396–402.Google Scholar
  21. 21.
    Musina RA, Belyavski AV, Tarusova OV, Solovyova EV, Sukhikh GT. Endometrial mesenchymal stem cells isolated from the menstrual blood. Bull Exp Biol Med. 2008;145(4):539–43.Google Scholar
  22. 22.
    Kotobuki N, Hirose M, Takakura Y, Ohgushi H. Cultured autologous human cells for hard tissue regeneration: preparation and characterization of mesenchymal stem cells from bone marrow. Artif Organs. 2004;28(1):33–9.Google Scholar
  23. 23.
    Yu G, Wu X, Dietrich MA, Polk P, Scott LK, Ptitsyn AA, et al. Yield and characterization of subcutaneous human adipose-derived stem cells by flow cytometric and adipogenic mRNA analyzes. Cytotherapy. 2010;12(4):538–46.  https://doi.org/10.3109/14653241003649528.Google Scholar
  24. 24.
    Woo DH, Hwang HS, Shim JH. Comparison of adult stem cells derived from multiple stem cell niches. Biotechnol Lett. 2016;38(5):751–9.  https://doi.org/10.1007/s10529-016-2050-2.Google Scholar
  25. 25.
    Mohamed-Ahmed S, Fristad I, Lie SA, Suliman S, Mustafa K, Vindenes H, et al. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018;9(1):168.  https://doi.org/10.1186/s13287-018-0914-1.Google Scholar
  26. 26.
    Arufe MC, De la Fuente A, Fuentes I, Toro FJ, Blanco FJ. Umbilical cord as a mesenchymal stem cell source for treating joint pathologies. World J Orthop. 2011;2(6):43–50.  https://doi.org/10.5312/wjo.v2.i6.43.Google Scholar
  27. 27.
    Wu KH, Chan CK, Tsai C, Chang YH, Sieber M, Chiu TH, et al. Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation. 2011;91(12):1412–6.  https://doi.org/10.1097/TP.0b013e31821aba18.Google Scholar
  28. 28.
    Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–67.  https://doi.org/10.1681/ASN.2008070798.Google Scholar
  29. 29.
    Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev. 2015;11(1):150–60.  https://doi.org/10.1007/s12015-014-9545-9.Google Scholar
  30. 30.
    Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499–506.  https://doi.org/10.1182/blood-2007-02-069716.Google Scholar
  31. 31.
    Francois M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol. Ther. : the journal of the American Society of Gene Therapy. 2012;20(1):187–95.  https://doi.org/10.1038/mt.2011.189.Google Scholar
  32. 32.
    Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells. 2013;31(10):2042–6.  https://doi.org/10.1002/stem.1400.Google Scholar
  33. 33.
    Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402.  https://doi.org/10.1016/j.stem.2013.09.006.Google Scholar
  34. 34.
    Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35(5):1482–90.  https://doi.org/10.1002/eji.200425405.Google Scholar
  35. 35.
    • Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009–16.  https://doi.org/10.1038/ni.3002 Describes the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation.Google Scholar
  36. 36.
    Gao WX, Sun YQ, Shi J, Li CL, Fang SB, Wang D, et al. Effects of mesenchymal stem cells from human induced pluripotent stem cells on differentiation, maturation, and function of dendritic cells. Stem Cell Res Ther. 2017;8(1):48.  https://doi.org/10.1186/s13287-017-0499-0.Google Scholar
  37. 37.
    Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(12):1312–20.  https://doi.org/10.1097/TP.0b013e3181fed001.Google Scholar
  38. 38.
    Su J, Chen X, Huang Y, Li W, Li J, Cao K, et al. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ. 2014;21(3):388–96.  https://doi.org/10.1038/cdd.2013.149.Google Scholar
  39. 39.
    Milner CM, Day AJ. TSG-6: a multifunctional protein associated with inflammation. J Cell Sci. 2003;116(Pt 10):1863–73.  https://doi.org/10.1242/jcs.00407.Google Scholar
  40. 40.
    Wisniewski HG, Vilcek J. Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14. Cytokine Growth Factor Rev. 2004;15(2–3):129–46.  https://doi.org/10.1016/j.cytogfr.2004.01.005.Google Scholar
  41. 41.
    Day AJ, Milner CM. TSG-6: a multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biol : journal of the International Society for Matrix Biology. 2018.  https://doi.org/10.1016/j.matbio.2018.01.011.
  42. 42.
    Romano B, Elangovan S, Erreni M, Emanuela S, Petti L, Kunderfranco P, et al. TNF-stimulated gene-6 (TSG-6) is a key regulator in switching stemness and biological properties of mesenchymal stem cells. Stem Cells. 2019. doi: https://doi.org/10.1002/stem.3010.
  43. 43.
    Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63.  https://doi.org/10.1016/j.stem.2009.05.003.Google Scholar
  44. 44.
    Lee RH, Yu JM, Foskett AM, Peltier G, Reneau JC, Bazhanov N, et al. TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc Natl Acad Sci U S A. 2014;111(47):16766–71.  https://doi.org/10.1073/pnas.1416121111.Google Scholar
  45. 45.
    He Z, Hua J, Qian D, Gong J, Lin S, Xu C, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-alpha stimulated gene/protein 6. Sci Rep. 2016;6:38438.  https://doi.org/10.1038/srep38438.Google Scholar
  46. 46.
    Qi Y, Jiang D, Sindrilaru A, Stegemann A, Schatz S, Treiber N, et al. TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds. J Invest Dermatol. 2014;134(2):526–37.  https://doi.org/10.1038/jid.2013.328.Google Scholar
  47. 47.
    •• Sala E, Genua M, Petti L, Anselmo A, Arena V, Cibella J, et al. Mesenchymal stem cells reduce colitis in mice via release of TSG6, independently of their localization to the intestine. Gastroenterology. 2015;149(1):163–76 e20.  https://doi.org/10.1053/j.gastro.2015.03.013 Provides evidence that the therapeutic efficacy of MSCs in the treatment of colitis is independent of their homing properties, but is mediated by the release of soluble factors.Google Scholar
  48. 48.
    Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009;4(3):206–16.  https://doi.org/10.1016/j.stem.2009.02.001.Google Scholar
  49. 49.
    Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol. Ther. : the journal of the American Society of Gene Therapy. 2006;14(6):840–50.  https://doi.org/10.1016/j.ymthe.2006.05.016.Google Scholar
  50. 50.
    Iso Y, Spees JL, Serrano C, Bakondi B, Pochampally R, Song YH, et al. Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem Biophys Res Commun. 2007;354(3):700–6.  https://doi.org/10.1016/j.bbrc.2007.01.045.Google Scholar
  51. 51.
    Schuleri KH, Boyle AJ, Hare JM. Mesenchymal stem cells for cardiac regenerative therapy. Handb Exp Pharmacol. 2007;180:195–218.  https://doi.org/10.1007/978-3-540-68976-8_9.Google Scholar
  52. 52.
    Jung KH, Song SU, Yi T, Jeon MS, Hong SW, Zheng HM, et al. Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology. 2011;140(3):998–1008.  https://doi.org/10.1053/j.gastro.2010.11.047.Google Scholar
  53. 53.
    Haldar D, Henderson NC, Hirschfield G, Newsome PN. Mesenchymal stromal cells and liver fibrosis: a complicated relationship. FASEB J. : official publication of the Federation of American Societies for Experimental Biology. 2016;30(12):3905–28.  https://doi.org/10.1096/fj.201600433R.Google Scholar
  54. 54.
    Ciccocioppo R, Dos Santos CC, Baumgart DC, Cangemi GC, Cardinale V, Ciacci C, et al. Proceedings of the signature series event of the international society for cellular therapy: “advancements in cellular therapies and regenerative medicine in digestive diseases,” London, United Kingdom, May 3, 2017. Cytotherapy. 2018;20(3):461–76.  https://doi.org/10.1016/j.jcyt.2017.12.004.Google Scholar
  55. 55.
    Williams R, Alexander G, Aspinall R, Bosanquet J, Camps-Walsh G, Cramp M, et al. New metrics for the lancet standing commission on liver disease in the UK. Lancet. 2017;389(10083):2053–80.  https://doi.org/10.1016/S0140-6736(16)32234-6.Google Scholar
  56. 56.
    Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Asp Med 2019;65:37–55. doi: https://doi.org/10.1016/j.mam.2018.09.002.
  57. 57.
    Cao HJ, Wang MD, Li SG, Zhu L, Zheng JH. Paracrine effect of bone marrow mesenchymal stem cells on proliferation, apoptosis, and alpha-actin-2 expression in hepatic stellate cells. Genet. Mol. Res. 2017;16(1).  https://doi.org/10.4238/gmr16019201.
  58. 58.
    Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, et al. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007;363(2):247–52.  https://doi.org/10.1016/j.bbrc.2007.05.150.Google Scholar
  59. 59.
    Najimi M, Berardis S, El-Kehdy H, Rosseels V, Evraerts J, Lombard C, et al. Human liver mesenchymal stem/progenitor cells inhibit hepatic stellate cell activation: in vitro and in vivo evaluation. Stem Cell Res Ther. 2017;8(1):131.  https://doi.org/10.1186/s13287-017-0575-5.Google Scholar
  60. 60.
    Fiore E, Malvicini M, Bayo J, Peixoto E, Atorrasagasti C, Sierra R, et al. Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells. Stem Cell Res Ther. 2016;7(1):172.  https://doi.org/10.1186/s13287-016-0424-y.Google Scholar
  61. 61.
    Maggini J, Mirkin G, Bognanni I, Holmberg J, Piazzon IM, Nepomnaschy I, et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One. 2010;5(2):e9252.  https://doi.org/10.1371/journal.pone.0009252.Google Scholar
  62. 62.
    Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology. 2000;32(1):11–6.  https://doi.org/10.1053/jhep.2000.9124.Google Scholar
  63. 63.
    Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46(1):219–28.  https://doi.org/10.1002/hep.21704.Google Scholar
  64. 64.
    El Baz H, Demerdash Z, Kamel M, Atta S, Salah F, Hassan S, et al. Transplant of hepatocytes, undifferentiated mesenchymal stem cells, and in vitro hepatocyte-differentiated mesenchymal stem cells in a chronic liver failure experimental model: a comparative study. Exp. Clin. Transplant. : official journal of the Middle East Society for Organ Transplantation. 2018;16(1):81–9.  https://doi.org/10.6002/ect.2016.0226.Google Scholar
  65. 65.
    Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Deregibus MC, et al. Isolation and characterization of a stem cell population from adult human liver. Stem Cells. 2006;24(12):2840–50.  https://doi.org/10.1634/stemcells.2006-0114.Google Scholar
  66. 66.
    Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, Bagheri M, Bashtar M, Ghanaati H, et al. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med. 2007;10(4):459–66.Google Scholar
  67. 67.
    Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011;54(3):820–8.  https://doi.org/10.1002/hep.24434.Google Scholar
  68. 68.
    Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N, et al. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. Eur J Gastroenterol Hepatol. 2011;23(10):936–41.  https://doi.org/10.1097/MEG.0b013e3283488b00.Google Scholar
  69. 69.
    Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365(18):1713–25.  https://doi.org/10.1056/NEJMra1102942.Google Scholar
  70. 70.
    Ko IK, Kim BG, Awadallah A, Mikulan J, Lin P, Letterio JJ, et al. Targeting improves MSC treatment of inflammatory bowel disease. Mol. Ther. : the journal of the American Society of Gene Therapy. 2010;18(7):1365–72.  https://doi.org/10.1038/mt.2010.54.Google Scholar
  71. 71.
    Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, et al. Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther. 2008;326(2):523–31.  https://doi.org/10.1124/jpet.108.137083.Google Scholar
  72. 72.
    Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut. 2010;59(12):1662–9.  https://doi.org/10.1136/gut.2010.215152.Google Scholar
  73. 73.
    Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, et al. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012;61(3):468–9.  https://doi.org/10.1136/gutjnl-2011-300083.Google Scholar
  74. 74.
    Mayer L, Pandak WM, Melmed GY, Hanauer SB, Johnson K, Payne D, et al. Safety and tolerability of human placenta-derived cells (PDA001) in treatment-resistant Crohn’s disease: a phase 1 study. Inflamm Bowel Dis. 2013;19(4):754–60.  https://doi.org/10.1097/MIB.0b013e31827f27df.Google Scholar
  75. 75.
    Melmed GY, Pandak WM, Casey K, Abraham B, Valentine J, Schwartz D, et al. Human placenta-derived cells (PDA-001) for the treatment of moderate-to-severe Crohn’s disease: a phase 1b/2a study. Inflamm Bowel Dis. 2015;21(8):1809–16.  https://doi.org/10.1097/MIB.0000000000000441.Google Scholar
  76. 76.
    Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol. 2014;12(1):64–71.  https://doi.org/10.1016/j.cgh.2013.06.021.Google Scholar
  77. 77.
    Zhang J, Lv S, Liu X, Song B, Shi L. Umbilical cord mesenchymal stem cell treatment for Crohn’s disease: a randomized controlled clinical trial. Gut and liver. 2018;12(1):73–8.  https://doi.org/10.5009/gnl17035.Google Scholar
  78. 78.
    Dhere T, Copland I, Garcia M, Chiang KY, Chinnadurai R, Prasad M, et al. The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn’s disease - a phase 1 trial with three doses. Aliment Pharmacol Ther. 2016;44(5):471–81.  https://doi.org/10.1111/apt.13717.Google Scholar
  79. 79.
    Panes J, Rimola J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14(11):652–64.  https://doi.org/10.1038/nrgastro.2017.104.Google Scholar
  80. 80.
    Makowiec F, Jehle EC, Starlinger M. Clinical course of perianal fistulas in Crohn’s disease. Gut. 1995;37(5):696–701.Google Scholar
  81. 81.
    Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154(5):1334–42 e4.  https://doi.org/10.1053/j.gastro.2017.12.020.Google Scholar
  82. 82.
    Galleu A, Riffo-Vasquez Y, Trento C, Lomas C, Dolcetti L, Cheung TS, et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med. 2017;9(416).  https://doi.org/10.1126/scitranslmed.aam7828.
  83. 83.
    Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52(1):79–86.  https://doi.org/10.1007/DCR.0b013e3181973487.Google Scholar
  84. 84.
    Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60(6):788–98.  https://doi.org/10.1136/gut.2010.214841.Google Scholar
  85. 85.
    Mannon PJ. Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn’s disease. Expert Opin Biol Ther. 2011;11(9):1249–56.  https://doi.org/10.1517/14712598.2011.602967.Google Scholar
  86. 86.
    Cho YB, Park KJ, Yoon SN, Song KH, Kim DS, Jung SH, et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med. 2015;4(5):532–7.  https://doi.org/10.5966/sctm.2014-0199.Google Scholar
  87. 87.
    de la Portilla F, Alba F, Garcia-Olmo D, Herrerias JM, Gonzalez FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Color Dis. 2013;28(3):313–23.  https://doi.org/10.1007/s00384-012-1581-9.Google Scholar
  88. 88.
    Ciccocioppo R, Gallia A, Sgarella A, Kruzliak P, Gobbi PG, Corazza GR. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc. 2015;90(6):747–55.  https://doi.org/10.1016/j.mayocp.2015.03.023.Google Scholar
  89. 89.
    Garcia-Olmo D, Schwartz DA. Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn’s disease--going from bench to bedside. Gastroenterology. 2015;149(4):853–7.  https://doi.org/10.1053/j.gastro.2015.08.038.Google Scholar
  90. 90.
    Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2015;149(4):918–27 e6.  https://doi.org/10.1053/j.gastro.2015.06.014.Google Scholar
  91. 91.
    Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–90.  https://doi.org/10.1016/S0140-6736(16)31203-X.Google Scholar
  92. 92.
    Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, Lightner AL, et al. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2017;153(1):59–62 e2.  https://doi.org/10.1053/j.gastro.2017.04.001.Google Scholar
  93. 93.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48(7):1416–23.  https://doi.org/10.1007/s10350-005-0052-6.Google Scholar
  94. 94.
    Garcia-Olmo D, Herreros D, Pascual M, Pascual I, De-La-Quintana P, Trebol J, et al. Treatment of enterocutaneous fistula in Crohn’s disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Color Dis. 2009;24(1):27–30.  https://doi.org/10.1007/s00384-008-0559-0.Google Scholar
  95. 95.
    Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Color Dis. 2012;27(5):595–600.  https://doi.org/10.1007/s00384-011-1350-1.Google Scholar
  96. 96.
    Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369(9573):1641–57.  https://doi.org/10.1016/S0140-6736(07)60751-X.Google Scholar
  97. 97.
    Feagan BG, Chande N, MacDonald JK. Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? Evidence from cochrane reviews. Inflamm Bowel Dis. 2013;19(9):2031–40.  https://doi.org/10.1097/MIB.0b013e3182920108.Google Scholar
  98. 98.
    Panaccione R, Ghosh S, Middleton S, Marquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392–400 e3.  https://doi.org/10.1053/j.gastro.2013.10.052.Google Scholar
  99. 99.
    Jarnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlen P, Granno C, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005;128(7):1805–11.Google Scholar
  100. 100.
    Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462–76.  https://doi.org/10.1056/NEJMoa050516.Google Scholar
  101. 101.
    Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780–7.  https://doi.org/10.1136/gut.2010.221127.Google Scholar
  102. 102.
    Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85–95; quiz e14-5.  https://doi.org/10.1053/j.gastro.2013.05.048.Google Scholar
  103. 103.
    Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.  https://doi.org/10.1056/NEJMoa1215734.Google Scholar
  104. 104.
    Hu J, Zhao G, Zhang L, Qiao C, Di A, Gao H, et al. Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis. Exp Ther Med. 2016;12(5):2983–9.  https://doi.org/10.3892/etm.2016.3724.Google Scholar
  105. 105.
    Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823–36 e2.  https://doi.org/10.1016/j.cgh.2017.06.037.Google Scholar
  106. 106.
    • Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70–81.  https://doi.org/10.1016/S0140-6736(17)31796-8 This study reports the first in vivo evidence of MSCs as a new approach to treat severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver.Google Scholar
  107. 107.
    Van De Kamer JH, Weijers HA, Dicke WK. Coeliac disease. IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease. Acta Paediatr. 1953;42(3):223–31.Google Scholar
  108. 108.
    Lee AR, Ng DL, Diamond B, Ciaccio EJ, Green PH. Living with coeliac disease: survey results from the U.S.A. J Hum Nutr Diet : the official journal of the British Dietetic Association. 2012;25(3):233–8.  https://doi.org/10.1111/j.1365-277X.2012.01236.x.Google Scholar
  109. 109.
    Kaukinen K, Lindfors K, Maki M. Advances in the treatment of coeliac disease: an immunopathogenic perspective. Nat Rev Gastroenterol Hepatol. 2014;11(1):36–44.  https://doi.org/10.1038/nrgastro.2013.141.Google Scholar
  110. 110.
    Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, et al. Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol. 2009;218(3):350–9.  https://doi.org/10.1002/path.2535.Google Scholar
  111. 111.
    Semont A, Mouiseddine M, Francois A, Demarquay C, Mathieu N, Chapel A, et al. Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis. Cell Death Differ. 2010;17(6):952–61.  https://doi.org/10.1038/cdd.2009.187.Google Scholar
  112. 112.
    Tayman C, Uckan D, Kilic E, Ulus AT, Tonbul A, Murat Hirfanoglu I, et al. Mesenchymal stem cell therapy in necrotizing enterocolitis: a rat study. Pediatr Res. 2011;70(5):489–94.  https://doi.org/10.1203/PDR.0b013e31822d7ef2.Google Scholar
  113. 113.
    Ciccocioppo R, Di Sabatino A, Parroni R, Muzi P, D'Alo S, Ventura T, et al. Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease. Am J Clin Pathol. 2001;115(4):494–503.  https://doi.org/10.1309/UV54-BHP3-A66B-0QUD.Google Scholar
  114. 114.
    Ciccocioppo R, Camarca A, Cangemi GC, Radano G, Vitale S, Betti E, et al. Tolerogenic effect of mesenchymal stromal cells on gliadin-specific T lymphocytes in celiac disease. Cytotherapy. 2014;16(8):1080–91.  https://doi.org/10.1016/j.jcyt.2014.03.002.Google Scholar
  115. 115.
    Ciccocioppo R, Gallia A, Avanzini MA, Betti E, Picone C, Vanoli A, et al. A refractory celiac patient successfully treated with mesenchymal stem cell infusions. Mayo Clin Proc. 2016;91(6):812–9.  https://doi.org/10.1016/j.mayocp.2016.03.001.Google Scholar
  116. 116.
    Ciccocioppo R, Russo ML, Bernardo ME, Biagi F, Catenacci L, Avanzini MA, et al. Mesenchymal stromal cell infusions as rescue therapy for corticosteroid-refractory adult autoimmune enteropathy. Mayo Clin Proc. 2012;87(9):909–14.  https://doi.org/10.1016/j.mayocp.2012.04.014.Google Scholar
  117. 117.
    Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G. Autoimmune enteropathy and villous atrophy in adults. Lancet. 1997;350(9071):106–9.  https://doi.org/10.1016/S0140-6736(97)01042-8.Google Scholar
  118. 118.
    Naymagon S, Naymagon L, Wong SY, Ko HM, Renteria A, Levine J, et al. Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol. 2017;14(12):711–26.  https://doi.org/10.1038/nrgastro.2017.126.Google Scholar
  119. 119.
    Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95(9):2754–9.Google Scholar
  120. 120.
    Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–41.  https://doi.org/10.1016/S0140-6736(04)16104-7.Google Scholar
  121. 121.
    Locatelli F, Algeri M, Trevisan V, Bertaina A. Remestemcel-L for the treatment of graft versus host disease. Expert Rev Clin Immunol. 2017;13(1):43–56.  https://doi.org/10.1080/1744666X.2016.1208086.Google Scholar
  122. 122.
    Bernardo ME, Fibbe WE. Mesenchymal stromal cells and hematopoietic stem cell transplantation. Immunol Lett. 2015;168(2):215–21.  https://doi.org/10.1016/j.imlet.2015.06.013.Google Scholar
  123. 123.
    Kurtzberg J, Prockop S, Teira P, Bittencourt H, Lewis V, Chan KW et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Clin Gastroenterol Hepatol. 2014;20(2):229–235. doi: https://doi.org/10.1016/j.bbmt.2013.11.001.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Barbara Romano
    • 1
  • Ana Lleo
    • 2
    • 3
  • Emanuela Sala
    • 4
  • Giovanna D’Amico
    • 5
  • Domenica Ida Marino
    • 6
  • Rachele Ciccocioppo
    • 7
  • Stefania Vetrano
    • 2
    • 4
    Email author
  1. 1.Department of Pharmacy, School of Medicine and SurgeryUniversity of Naples Federico IINaplesItaly
  2. 2.Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly
  3. 3.Division of Internal Medicine and HepatologyHumanitas Clinical and Research Center IRCCSRozzanoItaly
  4. 4.IBD Center, Laboratory of Immunology in GastroenterologyHumanitas Clinical and Research Center IRCCSRozzanoItaly
  5. 5.“Centro Ricerca Tettamanti” Pediatric Department, University of Milano-Bicocca, Fondazione MBBMMonzaItaly
  6. 6.Ohio State College of Arts and ScienceColumbusUSA
  7. 7.Gastroenterology Unit, Department of MedicineAOUI Policlinico G.B. Rossi and University of VeronaVeronaItaly

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