Topical Implantation of Mesenchymal Stem Cells Has Beneficial Effects on Healing of Experimental Colitis in Rats

Abstract

Mesenchymal stem cells (MSCs) are attractive cell sources in regenerative medicine. We examined the effects of topical MSCs implantation on an experimental model of inflammatory bowel disease. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in vitro, were characterized by flow cytometry, reverse transcriptionpolymerase chain reaction, enzyme-linked immunosorbent assay, and differentiation assays. Experimental colitis was induced by intraluminal instillation of 2,4,6-trinitrobonzene sulfonic acid (TNBS) in the colons of male rats. The putative MSCs and unselected fresh bone marrow cells were injected into the colonic submucosa surrounding the area exposed to TNBS. The healing process of the injury was examined macroscopically and immunohistologically. Multipotent MSCs positive for CD29 and CD90, and negative for CD31 and CD34, were implanted into colon tissue surrounding the lesion; a majority of the engrafted cells were positive for vimentin. The implantation significantly accelerated healing of the damaged mucosa compared with vehicle-injected controls. The MSCs expressed vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-␤1 in vitro and after the implantation. In conclusion, we found that MSCs were successfully topically implanted in the colon and that they were associated with accelerated healing of TNBS-induced colitis. The beneficial effects of the MSCs might be mediated, at least in part, by their ability to differentiate into colonic interstitial cells and by their ability to provide VEGF and TGF-␤1 to the injured area.

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis

“…In our study, a single administration of MSCs or CM into the colon by enema restored inflammation-induced epithelial and goblet cell loss, as well as aiding repair of colonic architecture to control and sham-treated levels. Our results are consistent with previous studies involving IP and IV administration of MSCs, which reported reductions in gross morphological damage to the colon following MSC treatment (33,79).…”

“…In contrast to prior studies, using systemic IP and IV injections of MSCs, application by enema is less invasive and avoids the initial uptake and accumulation of MSCs within filtering organs, such as the lungs, liver, or spleen associated with IV and IP delivery (36). Direct injection of MSCs into the colonic wall has been investigated (33), but this is highly invasive and not clinically feasible. Application of MSCs by enema is safe, convenient, and minimally invasive, provid- ing a feasible option for administration in IBD patients without severe complications.…”

“…Clinical trials have demonstrated administration of MSCs as a safe and feasible treatment option for complex perianal fistulas associated with Crohn's disease (17,23). In experimental models of colitis, MSCs administered intraperitoneally (IP), intravenously (IV), or directly into the colonic wall have proven effective for tissue repair (13,33,79). However, the potential of MSCs to alter enteric neural dysfunction resulting from inflammation is unknown.…”

The Possible Role of Mesenchymal Stem Cells Therapy in the Repair of Experimentally Induced Colitis in Male Albino Rats

“…Additionally, it was suggested that in an earlier period, (i.e., on day 3 after the colitis induction) engrafted MSCs also differentiated into colonic interstitial lineage cells and produced vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGF-β1). Therefore, the authors suggested that MSCs may contribute, at least in a part, to the healing of injured colonic mucosa by secreting TGF-β1 and VEGF (28). In the present study ulceration, loss of surface columnar epithelial lining and huge lymphatic nodule piercing the muscularis mucosa were still recorded in colitis subgroup IIb (at 10 days).…”

“…It was suggested that bone marrow-derived cells are temporally and efficiently recruited into gastrointestinal tissue during the healing process of chemical injury (30). The involvement of the bone marrow-derived cells into gastrointestinal tissue reduces after the damage was completely healed, suggesting that the bone marrow derived cells participate positively in wound healing (28). Based upon immunofluorescence PKH26 labeled MSCs results of the current study and upon explanations of other investigators, MSCs were numerous three days after MSCs injection for promoting the healing process and then disappeared late at ten days as healing was completed and no further homing of MSCs cells.…”