Skip to main content

Advertisement

Log in

Use of Mesenchymal Stem Cells (MSC) in Chronic Inflammatory Fistulizing and Fibrotic Diseases: a Comprehensive Review

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Mesenchymal stem cells (MSC), multipotent adult stem cells, feature the potential to regenerate tissue damage and, in parallel, inhibit inflammation and fibrosis. MSC can be safely transplanted in autologous and allogeneic ways as they are non-immunogenic, and consequently represent a therapeutic option for refractory connective tissue diseases, fibrosing diseases like scleroderma and fistulizing colitis like in Crohn’s disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, and 22 are on autoimmune diseases. In irradiation-induced colitis, MSC accelerate functional recovery of the intestine and dampen the systemic inflammatory response. In order to provide rescue therapy for accidentally over-irradiated prostate cancer patients who underwent radiotherapy, allogeneic bone marrow-derived MSC from family donors were intravenously infused to three patients with refractory and fistulizing colitis resembling fistulizing Crohn’s disease. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhoea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets towards an increase of T regulatory cells and a decrease of activated effector T cells. The current data indicate that MSC represent a promising alternative strategy in the treatment of various immune-mediated diseases. Encouraging results have already been obtained from clinical trials in Crohn’s disease and SLE as well as from case series in systemic sclerosis. MSC represent a safe therapeutic measure for patients who suffer from chronic and fistulizing colitis. These findings are instructional for the management of refractory inflammatory bowel diseases that are characterized by similar clinical and immunopathological features.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Djouad F, Bony C, Haupl T et al (2005) Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells. Arthritis Res Ther 7:R1304–R1315

    Article  PubMed  CAS  Google Scholar 

  2. De Bari C, Dell’Accio F, Luyten FP (2001) Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum 44(1):85–95

    Article  PubMed  Google Scholar 

  3. Noel D, Caton D, Roche S et al (2008) Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. Exp Cell Res 314:1575–1584

    Article  PubMed  CAS  Google Scholar 

  4. Fickert S, Fiedler J, Brenner RE (2003) Identification, quantification and isolation of mesenchymal progenitor cells from osteoarthritic synovium by fluorescence automated cell sorting. Osteoarthr Cartil 11:790–800

    Article  PubMed  CAS  Google Scholar 

  5. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20

    Article  PubMed  Google Scholar 

  6. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75(3):389–397

    Article  PubMed  CAS  Google Scholar 

  7. Klyushnenkova E, Mosca JD, Zernetkina V et al (2005) T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 12:47–57

    Article  PubMed  CAS  Google Scholar 

  8. Rasmusson I, Ringden O, Sundberg B, Le Blanc K (2003) Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76:1208–1213

    Article  PubMed  Google Scholar 

  9. Rasmusson I (2006) Immune modulation by mesenchymal stem cells. Exp Cell Res 312:2169–2179

    Article  PubMed  CAS  Google Scholar 

  10. Tokoyoda K, Zehentmeier S, Hegazy AN et al (2009) Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30:721–730

    Article  PubMed  CAS  Google Scholar 

  11. Chen L, Tredget EE, Wu PY, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3:e1886

    Article  PubMed  Google Scholar 

  12. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822

    Article  PubMed  CAS  Google Scholar 

  13. Nemeth K, Leelahavanichkul A, Yuen PS et al (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49

    Article  PubMed  CAS  Google Scholar 

  14. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113:6576–6583

    Article  PubMed  CAS  Google Scholar 

  15. Djouad F, Charbonnier LM, Bouffi C et al (2007) Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 25:2025–2032

    Article  PubMed  CAS  Google Scholar 

  16. Jiang XX, Zhang Y, Liu B et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126

    Article  PubMed  CAS  Google Scholar 

  17. Ren G, Su J, Zhang L et al (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27:1954–1962

    Article  PubMed  CAS  Google Scholar 

  18. Sato K, Ozaki K, Oh I et al (2007) Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109:228–234

    Article  PubMed  CAS  Google Scholar 

  19. Nasef A, Mathieu N, Chapel A et al (2007) Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84:231–237

    Article  PubMed  CAS  Google Scholar 

  20. Nasef A, Zhang YZ, Mazurier C et al (2009) Selected Stro-1-enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation. Int J Lab Hematol 31:9–19

    Article  PubMed  CAS  Google Scholar 

  21. Prevosto C, Zancolli M, Canevali P, Zocchi MR, Poggi A (2007) Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica 92:881–888

    Article  PubMed  CAS  Google Scholar 

  22. Parekkadan B, Tilles AW, Yarmush ML (2008) Bone marrow-derived mesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells. Stem Cells 26:1913–1919

    Article  PubMed  Google Scholar 

  23. Zappia E, Casazza S, Pedemonte E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761

    Article  PubMed  CAS  Google Scholar 

  24. Zhou H, Jin Z, Liu J, Yu S, Cui Q, Yi D (2008) Mesenchymal stem cells might be used to induce tolerance in heart transplantation. Med Hypotheses 70:785–787

    Article  PubMed  CAS  Google Scholar 

  25. Haniffa MA, Wang XN, Holtick U et al (2007) Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 179:1595–1604

    PubMed  CAS  Google Scholar 

  26. Corcione A, Benvenuto F, Ferretti E et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372

    Article  PubMed  CAS  Google Scholar 

  27. Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M (2009) Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 60:1006–1019

    Article  PubMed  CAS  Google Scholar 

  28. Malgieri A, Kantzari E, Patrizi MP, Gambardella S (2010) Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med 3:248–26

    PubMed  Google Scholar 

  29. Voswinkel, J., and Chapel, A. (2012). Mesenchymal stem cells and rheumatism: state of the art. Z Rheumatol.

  30. Beggs KJ, Lyubimov A, Borneman JN et al (2006) Immunologic consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons. Cell Transplant 15:711–721

    Article  PubMed  Google Scholar 

  31. Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262:509–525

    Article  PubMed  Google Scholar 

  32. Rubio D, Garcia-Castro J, Martin MC et al (2005) Spontaneous human adult stem cell transformation. Cancer Res 65:3035–3039

    PubMed  CAS  Google Scholar 

  33. Tarte K, Gaillard J, Lataillade JJ et al (2010) Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood 115:1549–1553

    Article  PubMed  CAS  Google Scholar 

  34. Bernardo ME, Zaffaroni N, Novara F et al (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67:9142–9149

    Article  PubMed  CAS  Google Scholar 

  35. Liang J, Zhang H, Hua B et al (2010) Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 69:1423–1429

    Article  PubMed  Google Scholar 

  36. Sun L, Wang D, Liang J et al (2010) Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 62:2467–2475

    Article  PubMed  CAS  Google Scholar 

  37. Dryden GW (2009) Overview of stem cell therapy for Crohn’s disease. Expert Opin Biol Ther 9:841–847

    Article  PubMed  CAS  Google Scholar 

  38. Dryden GW Jr (2009) Overview of biologic therapy for Crohn’s disease. Expert Opin Biol Ther 9:967–974

    Article  PubMed  CAS  Google Scholar 

  39. Ditschkowski M, Einsele H, Schwerdtfeger R et al (2003) Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation. Transplantation 75:1745–1747

    Article  PubMed  Google Scholar 

  40. Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA (2005) A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 48:1416–1423

    Article  PubMed  Google Scholar 

  41. Garcia-Olmo D, Herreros D, Pascual I et al (2009) Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 52:79–86

    Article  PubMed  Google Scholar 

  42. Garcia-Olmo D, Herreros D, Pascual M et al (2009) Treatment of enterocutaneous fistula in Crohn’s disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis 24:27–30

    Article  PubMed  Google Scholar 

  43. Garcia-Olmo D, Herreros D, De-La-Quintana P et al (2010) Adipose-derived stem cells in Crohn’s rectovaginal fistula. Case Report Med 2010:961758

    CAS  Google Scholar 

  44. Duijvestein M, Vos AC, Roelofs H et al (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59:1662–1669

    Article  PubMed  Google Scholar 

  45. Lazebnik LB, Konopliannikov AG, Kniazev OV et al (2010) Use of allogeneic mesenchymal stem cells in the treatment of intestinal inflammatory diseases. Ter Arkh 82:38–43

    PubMed  CAS  Google Scholar 

  46. Ciccocioppo R, Bernardo ME, Sgarella A et al (2011) Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulizing Crohn’s disease. Gut 60:788–798

    Article  PubMed  Google Scholar 

  47. Cipriani P, Guiducci S, Miniati I et al (2007) Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. Arthritis Rheum 56:1994–2004

    Article  PubMed  CAS  Google Scholar 

  48. Larghero J, Farge D, Braccini A et al (2008) Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis. Ann Rheum Dis 67:443–449

    Article  PubMed  CAS  Google Scholar 

  49. Keyszer G, Christopeit M, Fick S et al (2011) Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases. Arthritis Rheum 63:2540–2542

    Article  PubMed  Google Scholar 

  50. Deeg HJ (2007) How I treat refractory acute GVHD. Blood 109:4119–4126

    Article  PubMed  CAS  Google Scholar 

  51. Ringden O, Uzunel M, Rasmusson I et al (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81:1390–1397.52

    Article  PubMed  Google Scholar 

  52. Le Blanc K, Frassoni F, Ball L et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    Article  PubMed  Google Scholar 

  53. Potten CS, Owen G, Roberts SA (1990) The temporal and spatial changes in cell proliferation within the irradiated crypts of the murine small intestine. Int J Radiat Biol 57:185–199

    Article  PubMed  CAS  Google Scholar 

  54. Gaugler MH, Vereycken-Holler V, Squiban C, Vandamme M, Vozenin-Brotons MC, Benderitter M (2005) Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses. Radiat Res 163:479–487

    Article  PubMed  CAS  Google Scholar 

  55. Milliat F, Francois A, Isoir M et al (2006) Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages. Am J Pathol 169:1484–1495

    Article  PubMed  CAS  Google Scholar 

  56. Paris F, Fuks Z, Kang A et al (2001) Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293:293–297

    Article  PubMed  CAS  Google Scholar 

  57. Zhang J, Gong JF, Zhang W, Zhu WM, Li JS (2008) Effects of transplanted bone marrow mesenchymal stem cells on the irradiated intestine of mice. J Biomed Sci 15:585–594

    Article  PubMed  Google Scholar 

  58. Semont A, Francois S, Mouiseddine M et al (2006) Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol 585:19–30

    Article  PubMed  CAS  Google Scholar 

  59. Kudo K, Liu Y, Takahashi K et al (2010) Transplantation of mesenchymal stem cells to prevent radiation-induced intestinal injury in mice. J Radiat Res 51:73–79

    Article  PubMed  Google Scholar 

  60. Gao Z, Zhang Q, Han Y, Cheng X, Lu Y, Fan L, Wu Z (2012) Mesenchymal stromal cell-conditioned medium prevents radiation-induced small intestine injury in mice. Cytotherapy 14:267–273

    Article  PubMed  CAS  Google Scholar 

  61. Semont A, Mouiseddine M, Francois A et al (2010) Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis. Cell Death Differ 17:952–961

    Article  PubMed  CAS  Google Scholar 

  62. Lorenzi B, Pessina F, Lorenzoni P et al (2008) Treatment of experimental injury of anal sphincters with primary surgical repair and injection of bone marrow-derived mesenchymal stem cells. Dis Colon Rectum 51:411–420

    Article  PubMed  Google Scholar 

  63. Saha S, Bhanja P, Kabarriti R, Liu L, Alfieri AA, Guha C (2011) Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS One 6:e24072

    Article  PubMed  CAS  Google Scholar 

  64. Peiffert D, Simon JM, Eschwege F (2007) Epinal radiotherapy accident: passed, present, future. Cancer Radiother 11:309–312

    Article  PubMed  CAS  Google Scholar 

  65. Marchesi V, Aigle D, Peiffert D, Noel A, Simon JM (2009) Securitization of the bi-site radiotherapy activity as part of the resumption of treatments in the Hospital of Epinal by the team of Alexis Vautrin Nancy Cancer Center. Cancer Radiother 13:740–743

    Article  PubMed  CAS  Google Scholar 

  66. Choi EW, Shin IS, Park SY et al (2012) Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum 64:243–253

    Article  PubMed  CAS  Google Scholar 

  67. Von Korff M, Jensen MP, Karoly P (2000) Assessing global pain severity by self-report in clinical and health services research. Spine 25:3140–3151, Phila Pa 1976

    Article  Google Scholar 

  68. Tan G, Jensen MP, Thornby JI, Shanti BF (2004) Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain 5:133–137

    Article  PubMed  Google Scholar 

  69. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370

    Article  PubMed  CAS  Google Scholar 

  70. Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30:473–483

    Article  PubMed  Google Scholar 

  71. Sensebe L, Bourin P (2008) Producing MSC according GMP: process and controls. Biomed Mater Eng 18:173–177

    PubMed  Google Scholar 

Download references

Acknowledgments

Our special thanks to Professor Patrick Gourmelon, former head of the Radiological Protection and Human Health Division, Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, for providing the facilities and recruitment of patients; to Professor Jean-Jacques Lataillades, Burn Treatment Center, Percy Military Hospital, Clamart, Professor Luc Douay and Helene Rouard, Etablissement Français du Sang (EFS) for MSC production; Dr. Christian Guy-Coichard (Saint Antoine Hospital pain unit) for health and pain assessment and Dr. Jean-Yves Perrot (Saint Antoine Hospital immunology department) for his help in the technique of flow cytometry.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jan Voswinkel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Voswinkel, J., Francois, S., Simon, JM. et al. Use of Mesenchymal Stem Cells (MSC) in Chronic Inflammatory Fistulizing and Fibrotic Diseases: a Comprehensive Review. Clinic Rev Allerg Immunol 45, 180–192 (2013). https://doi.org/10.1007/s12016-012-8347-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-012-8347-6

Keywords

Navigation