Intraperitoneal but Not Intravenous Cryopreserved Mesenchymal Stromal Cells Home to the Inflamed Colon and Ameliorate Experimental Colitis

PLOS ONE, Dec 2019

Background and Aims Mesenchymal stromal cells (MSCs) were shown to have immunomodulatory activity and have been applied for treating immune-mediated disorders. We compared the homing and therapeutic action of cryopreserved subcutaneous adipose tissue (AT-MSCs) and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in rats with trinitrobenzene sulfonic acid (TNBS)–induced colitis. Methods After colonoscopic detection of inflammation AT-MSCs or BM-MSCs were injected intraperitoneally. Colonoscopic and histologic scores were obtained. Density of collagen fibres and apoptotic rates were evaluated. Cytokine levels were measured in supernatants of colon explants. For cell migration studies MSCs and skin fibroblasts were labelled with Tc-99m or CM-DiI and injected intraperitonealy or intravenously. Results Intraperitoneal injection of AT-MSCs or BM-MSCs reduced the endoscopic and histopathologic severity of colitis, the collagen deposition, and the epithelial apoptosis. Levels of TNF-α and interleukin-1β decreased, while VEGF and TGF-β did not change following cell-therapy. Scintigraphy showed that MSCs migrated towards the inflamed colon and the uptake increased from 0.5 to 24 h. Tc-99m-MSCs injected intravenously distributed into various organs, but not the colon. Cm-DiI-positive MSCs were detected throughout the colon wall 72 h after inoculation, predominantly in the submucosa and muscular layer of inflamed areas. Conclusions Intraperitoneally injected cryopreserved MSCs home to and engraft into the inflamed colon and ameliorate TNBS-colitis.

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Intraperitoneal but Not Intravenous Cryopreserved Mesenchymal Stromal Cells Home to the Inflamed Colon and Ameliorate Experimental Colitis

et al. (2012) Intraperitoneal but Not Intravenous Cryopreserved Mesenchymal Stromal Cells Home to the Inflamed Colon and Ameliorate Experimental Colitis. PLoS ONE 7(3): e33360. doi:10.1371/journal.pone.0033360 Intraperitoneal but Not Intravenous Cryopreserved Mesenchymal Stromal Cells Home to the Inflamed Colon and Ameliorate Experimental Colitis Morgana T. L. Castelo-Branco 0 Igor D. P. Soares 0 Daiana V. Lopes 0 Fernanda Buongusto 0 Cesonia A. 0 Martinusso 0 Alyson do Rosario Jr. 0 Sergio A. L. Souza 0 Bianca Gutfilen 0 Lea Mirian B. Fonseca 0 Celeste Elia 0 Kalil Madi 0 Alberto Schanaider 0 Maria Isabel D. Rossi 0 Heitor S. P. Souza 0 Silvana Allodi, Federal University of Rio de Janeiro, Brazil 0 1 Laborato rio de Imunologia Celular, Instituto de Ciencias Biome dicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil, 2 Laborato rio Multidisciplinar de Pesquisa , Departamento de Cl nica Me dica, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil, 3 Laborato rio de Imunohematologia , Departamento de Cl nica Me dica, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil , 4 Servic o de Medicina Nuclear, Laborato rio de Marcac a o de Ce lulas e Mole culas (LMCM), Departamento de Radiologia, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil, 5 Departamento de Patologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 6 Laborato rio de Cirurgia Experimental , Departamento de Cirurgia, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil Background and Aims: Mesenchymal stromal cells (MSCs) were shown to have immunomodulatory activity and have been applied for treating immune-mediated disorders. We compared the homing and therapeutic action of cryopreserved subcutaneous adipose tissue (AT-MSCs) and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods: After colonoscopic detection of inflammation AT-MSCs or BM-MSCs were injected intraperitoneally. Colonoscopic and histologic scores were obtained. Density of collagen fibres and apoptotic rates were evaluated. Cytokine levels were measured in supernatants of colon explants. For cell migration studies MSCs and skin fibroblasts were labelled with Tc-99m or CM-DiI and injected intraperitonealy or intravenously. Results: Intraperitoneal injection of AT-MSCs or BM-MSCs reduced the endoscopic and histopathologic severity of colitis, the collagen deposition, and the epithelial apoptosis. Levels of TNF-a and interleukin-1b decreased, while VEGF and TGF-b did not change following cell-therapy. Scintigraphy showed that MSCs migrated towards the inflamed colon and the uptake increased from 0.5 to 24 h. Tc-99m-MSCs injected intravenously distributed into various organs, but not the colon. Cm-DiIpositive MSCs were detected throughout the colon wall 72 h after inoculation, predominantly in the submucosa and muscular layer of inflamed areas. Conclusions: Intraperitoneally injected cryopreserved MSCs home to and engraft into the inflamed colon and ameliorate TNBS-colitis. - Funding: This work was supported by grants from the Brazilian Research Council (CNPq, http://www.cnpq.br/) and the FAPERJ (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro, http://www.faperj.br/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Inflammatory bowel disease (IBD) comprises a spectrum of chronic and relapsing diseases including Crohns disease (CD) and ulcerative colitis. CD is characterized by a background of mucosal T-cell dysfunction, inflammatory cell infiltration, and abnormal cytokine production leading to uncontrolled and persistent intestinal transmural inflammation [1]. Although the aetiology of CD remains unknown, there is evidence indicating the existence of an abnormal immune response against the gut comensal microbiota [2]. However, despite all recent scientific advances in the study of IBD, available therapies for CD are still largely based on non-specific immunosuppressive agents, and continue to have limited efficacy with major concerns regarding safety issues [3]. Indeed, this illustrates the need for investigating new therapeutic alternatives to dampen local inflammation, both effectively modulating Th1-driven response and restoring the integrity of the mucosal barrier. Mesenchymal stromal cells (MSCs) are adult somatic cells that reside in the stroma of solid organs and are considered as precursors of non-haematopoietic connective tissues. MSCs have been demonstrated to differentiate into cells of mesodermal lineage such as bone, cartilage, and fat [4]. Recently, MSC have been explored in regenerative medicine due not only to their differentiation potential but mostly to the capacity to improve the repair of damaged tissues b (...truncated)


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Morgana T. L. Castelo-Branco, Igor D. P. Soares, Daiana V. Lopes, Fernanda Buongusto, Cesonia A. Martinusso, Alyson do Rosario, Sergio A. L. Souza, Bianca Gutfilen, Lea Mirian B. Fonseca, Celeste Elia, Kalil Madi, Alberto Schanaider, Maria Isabel D. Rossi, Heitor S. P. Souza. Intraperitoneal but Not Intravenous Cryopreserved Mesenchymal Stromal Cells Home to the Inflamed Colon and Ameliorate Experimental Colitis, PLOS ONE, 2012, Volume 7, Issue 3, DOI: 10.1371/journal.pone.0033360