Allogeneic Bone Marrow L Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn ’ s Disease

BACKGROUND & AIMS: Patients with perianal fi stulizing Crohn ’ s disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone marrow (cid:1) derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. METHODS: Twenty-one patients with refractory perianal fi stulizing Crohn ’ s disease were randomly assigned to groups given injections of 1 (cid:3) 10 7 (n ¼ 5, group 1), 3 (cid:3) 10 7 (n ¼ 5, group 2), or 9 (cid:3) 10 7 (n ¼ 5, group 3) MSCs, or placebo (solution with no cells, n ¼ 6), perianal fi stulizing Crohn ’ s disease. Injection of 3 (cid:3) 10 7 MSCs appeared to promote healing of perianal fi stulas. ClinicalTrials.gov ID NCT01144962. In fl ammatory Bowel Disease.

[1]  I. Molendijk,et al.  Disappointing Durable Remission Rates in Complex Crohn's Disease Fistula , 2014, Inflammatory bowel diseases.

[2]  Y. Cho,et al.  Autologous adipose tissue‐derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula , 2013, Stem cells.

[3]  W. Fibbe,et al.  Mesenchymal stromal cells: sensors and switchers of inflammation. , 2013, Cell stem cell.

[4]  W. Fibbe,et al.  Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti‐inflammatory macrophages , 2013, Stem cells.

[5]  W. Fibbe,et al.  Multipotent stromal cells skew monocytes towards an anti-inflammatory function: the link with key immunoregulatory molecules , 2013, Haematologica.

[6]  W. Fibbe,et al.  Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6 , 2013, Haematologica.

[7]  D. García-Olmo,et al.  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 , 2013, International Journal of Colorectal Disease.

[8]  Y. Cho,et al.  Autologous Adipose Tissue-Derived Stem Cells for the Treatment of Crohn's Fistula: A Phase I Clinical Study , 2013, Cell transplantation.

[9]  Joshua M Hare,et al.  Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. , 2012, JAMA.

[10]  J. Marshall,et al.  Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials , 2012, PloS one.

[11]  D. Hommes,et al.  Immunomodulatory Effects of Mesenchymal Stromal Cells in Crohn's Disease , 2012, Journal of allergy.

[12]  H. Guadalajara,et al.  Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas , 2012, International Journal of Colorectal Disease.

[13]  S. Karaman,et al.  Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells , 2012, Annals of Hematology.

[14]  P. Moayyedi,et al.  Efficacy of Biological Therapies in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis , 2011, The American Journal of Gastroenterology.

[15]  H. Tilg,et al.  The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations. , 2010, Journal of Crohn's & colitis.

[16]  L. Moretta,et al.  MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. , 2009, Blood.

[17]  Wolfgang Wagner,et al.  Aging and Replicative Senescence Have Related Effects on Human Stem and Progenitor Cells , 2009, PloS one.

[18]  J. Gorman,et al.  Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. , 2009, The Annals of thoracic surgery.

[19]  D. García-Olmo,et al.  Expanded Adipose-Derived Stem Cells for the Treatment of Complex Perianal Fistula: a Phase II Clinical Trial , 2009, Diseases of the colon and rectum.

[20]  E. Jones,et al.  Age-related changes in human bone marrow-derived mesenchymal stem cells: Consequences for cell therapies , 2008, Mechanisms of Ageing and Development.

[21]  D. García-Olmo,et al.  A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation , 2005, Diseases of the colon and rectum.

[22]  D. Mevorach,et al.  Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. , 2005, Blood.

[23]  E. Kuipers,et al.  Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn's disease with infliximab: a double‐blind placebo‐controlled study , 2004, Alimentary pharmacology & therapeutics.

[24]  S. Hanauer,et al.  AGA technical review on perianal Crohn's disease. , 2003, Gastroenterology.

[25]  A. Zinsmeister,et al.  The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. , 2002, Gastroenterology.

[26]  G. Hellers,et al.  Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. , 1980, Gut.

[27]  M. Picco.  Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease , 2011 .

[28]  S. Ng,et al.  Perianal fistulizing Crohn's disease: a call to action. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.