The Transdifferentiation of Bone-Marrow-Derived Cells in Colonic Mucosal Regeneration after Dextran-Sulfate-Sodium-Induced Colitis in Mice

Abstract

Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed α-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs.

Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

“…Both in animal models as well as in patients, it seems that BMCs are involved in the healing process after intestinal injury. 20,[31][32][33][34] In our work, we detected BM-transplanted cells in the intestine, suggesting that another effect, rather than immunosuppression, may also contribute to regeneration or modulation of the local inflammatory response, as cytokine interplay was somewhat different between both treated groups. In accordance, biopsy specimens from the gastrointestinal tract of women who had received male BM transplants presented donor-derived epithelial cells in every part of the gastrointestinal tract.…”

Mesenchymal Stem Cells Recruit Macrophages to Alleviate Experimental Colitis Through TGFβ1

“…TGFβ1 receptor signaling has been shown to play an essential role during the pathogenesis and recovery of inflammation-related colitis [3,4,5,6,7], but through unclear mechanism. Also, MSCs transplantation has been reported to promote the recovery from DSS-induced colitis [9,10,11,12], whereas the underlying molecular mechanisms remain largely undefined.…”

“…However, the precise mechanisms have not been completely clarified. Recently, transplantation of bone-marrow derived cells, or particularly mesenchymal stem cells (MSCs), has been found to reduce the severity of, and improve the recovery from DSS-induced colitis [9,10,11,12]. Moreover, modulated TGFβ receptor signaling by MSCs in the injured colon has been indicated as a cause for the effect of MSCs [12], whereas the exact sources for TGFβ receptor ligands are not defined, and a direct causal link has not been proved.…”

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

“…Other studies have shown that bone marrow-derived cells contribute to the healing of gastrointestinal wounds in humans (Okamoto et al, 2002;Matsumoto et al, 2005) and animals (Brittan et al, 2002(Brittan et al, , 2005Komori et al, 2005a,b;Bamba et al, 2006;Hayashi et al, 2007;Khalil et al, 2007). Moreover, bone marrow-derived cells are recruited more efficiently to the injured gut than to a healthy gut, suggesting a rescue response for assisting with the recovery from damage (Komori et al, 2005a,b).…”