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Mesenchymal stem cell therapy for inflammatory bowel disease: An updated review with maintenance of remission Maneesh Dave, MD, MPH1, Palashkumar Jaiswal, MBBS2, Fabio Cominelli, MD, PhD1 Author Affiliations: 1 Division of Gastroenterology and Liver Disease, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA. 2 Division of Internal Medicine, John H Stroger Jr. Hospital of Cook County, Chicago, Illinois, USA Corresponding Author: Maneesh Dave, MD, MPH Division of Gastroenterology and Liver Disease Case Western Reserve University University Hospitals Case Medical Center 11100 Euclid Avenue, Cleveland Ohio 44106-5066 Phone # 216-844-1995 Fax# 216-844-7371 Email: [email protected] Word Count: 194 words Supplementary text Method Using our previously published research strategy, a systematic search of English and nonEnglish articles was performed with aid of PubMed (from 01/2015 to present) and Ovid (from 01/2015 to present) (1). We also identified additional studies by searching bibliographies and abstracts presented at the Digestive Disease Week, American College of Gastroenterology, European Crohn’s and Colitis Organization and United European Gastroenterology Week from 2015-2016. In order to increase the sensitivity of our search, we used free text words and MeSH terms with and without Boolean operators (“AND” and “OR”). Studies were selected based on the following inclusion criteria: (1) human studies, (2) included patients with IBD, (3) MSCs were used for treatment of IBD, and (4) peer-reviewed article, letter, or abstract. Exclusion criteria were (1) non-human studies and (2) use of total-body irradiation or myeloablative regimen. With this particular search strategy, we found an additional 67 peer-reviewed articles published since our previous publication and of these only 8 studies met the selection criteria. From meeting abstracts and bibliographies we were able to find 2 more studies that have satisfied our criteria. Human and murine MSCs suppress inflammation in murine models of intestinal inflammation Multiple studies have demonstrated that murine derived adipose and bone marrow mesenchymal stem cells (MSCs) can suppress inflammation in murine models of colonic inflammation(2-5). Similarly, human MSCs from different sources have also been utilized to treat inflammation in models of colonic inflammation in immune competent mice (supplementary table 1 for details) (6-11). However, ambiguities in immunosuppressive property of MSCs are still present and despite the data showing efficacy of human MSCs in treating inflammation in mice; many investigators have questioned the rationale of using human cells in immunocompetent mice (12). In the following section, we will briefly provide the advantages and disadvantages of modeling human vs mice MSCs in preclinical models of intestinal inflammation (13). Modeling human and murine MSCs in preclinical models of disease Human and murine MSCs are considered immune-evasive and characteristically have low expression of MHC II and costimulatory molecules- CD40, CD80 and CD86(14, 15). Despite species compatibility, murine MSCs have many disadvantages for in vivo therapeutic studies as 1) it is very difficult to isolate a pure population of MSCs from bone marrow that are not contaminated with other cells of mesenchymal lineage and, 2) in culture, murine MSCs tend to immortalize and have genomic instability (16, 17). On the other hand, it is much easier to isolate and propagate a pure population of human MSCs without genomic instability(13). A disadvantage of using human cells in immunocompetent mice is the possibility of immune rejection of human MSCs, though some studies have not found induction of immunological response against human MSCs in murine models of colitis and this area needs further study (4). Another challenging aspect of modeling MSC is that murine and human MSCs may not be identical in their dominant mechanism (s) of immunosuppression and healing as is demonstrated by indoleamine 2,3-dioxygenase (18, 19)_ENREF_20, an important pathway in human but not murine MSCs in immunosuppression (20). Therefore, to overcome these challenges a comparative biology approach to model human and murine MSCs in animal models has been suggested. This approach involves treating a model of intestinal inflammation with both murine and human MSCs for identification of the shared and differentially operating molecules and pathways that contribute to healing with a focus on common pathways (eg prostaglandin E2) for murine and human MSC. Another methodology, which is still in infancy, but could be developed, is to use humanized mice for testing different regenerative medicine therapies including MSCs for treatment of intestinal inflammation (21). We believe that a combination of these approaches can overcome most of the limitations of modeling MSCs in mice, helping to generate important mechanistic preclinical data to guide human MSC therapy and identify novel molecules that promote tissue regeneration and healing. References 1. Dave M, Mehta K, Luther J, Baruah A, Dietz AB, Faubion WA, Jr. Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2015;21(11):2696-707. 2. Anderson P, Souza-Moreira L, Morell M, Caro M, O'Valle F, Gonzalez-Rey E, et al. Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis. Gut. 2013 Aug;62(8):1131-41. 3. Ondrej Ryska ZS, Ondrej Mestak, Eva Matouskova, Pavel Vesely, Iveta, Mrazova. Local Application of Adipose-Derived Mesenchymal Stem Cells Can Lead toIntestinal Fistula Healing - Experimental Study. Gastroenteroloy. 2015;Volume 148(4):S 691. 4. 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. 5. Dave M, Hayashi Y, Gajdos GB, Smyrk TC, Svingen PA, Kvasha SM, et al. Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion. Gastroenterology. 2015;148(5):978-90. 6. Banerjee A, Bizzaro D, Burra P, Di Liddo R, Pathak S, Arcidiacono D, et al. Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice. Stem Cell Res Ther. 2015;6:79. 7. Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(3):978-89. 8. Jung WY, Kang JH, Kim KG, Kim HS, Jang BI, Park YH, et al. Human adipose-derived stem cells attenuate inflammatory bowel disease in IL-10 knockout mice. Tissue Cell. 2015;47(1):86-93. 9. Kim HS, Shin TH, Lee BC, Yu KR, Seo Y, Lee S, et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology. 2013;145(6):1392-403 e1-8. 10. Li L, Liu S, Xu Y, Zhang A, Jiang J, Tan W, et al. Human Umbilical Cord-Derived Mesenchymal Stem Cells Downregulate Inflammatory Responses by Shifting the Treg/Th17 Profile in Experimental Colitis. Pharmacology. 2013;92(5-6):257-64. 11. Tang RJ, Shen SN, Zhao XY, Nie YZ, Xu YJ, Ren J, et al. Mesenchymal stem cellsregulated Treg cells suppress colitis-associated colorectal cancer. Stem Cell Res Ther. 2015;6:71. 12. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35-42. 13. Chinnadurai R, Ng S, Velu V, Galipeau J. Challenges in animal modelling of mesenchymal stromal cell therapy for inflammatory bowel disease. World J Gastroenterol. 2015;21(16):4779-87. 14. Koppula PR, Chelluri LK, Polisetti N, Vemuganti GK. Histocompatibility testing of cultivated human bone marrow stromal cells - a promising step towards pre-clinical screening for allogeneic stem cell therapy. Cell Immunol. 2009;259(1):61-5. 15. Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L, Therapy MSCCotISfC. Immunological characterization of multipotent mesenchymal stromal cells--The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy. 2013;15(9):1054-61. 16. Dennis JE, Merriam A, Awadallah A, Yoo JU, Johnstone B, Caplan AI. A quadripotential mesenchymal progenitor cell isolated from the marrow of an adult mouse. J Bone Miner Res. 1999;14(5):700-9. 17. Krishnappa V, Boregowda SV, Phinney DG. The peculiar biology of mouse mesenchymal stromal cells--oxygen is the key. Cytotherapy. 2013;15(5):536-41. 18. Rodriguez-Palacios A, Kodani T, Kaydo L, Pietropaoli D, Corridoni D, Howell S, et al. Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes. Nature communications. 2015;6:7577. 19. 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 Jul;149(1):163-176.e20. 20. Ren G, Su J, Zhang L, Zhao X, Ling W, L'Huillie A, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells. 2009;27(8):1954-62. 21. Goettel JA, Biswas S, Lexmond WS, Yeste A, Passerini L, Patel B, et al. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood. 2015;125(25):3886-95.