The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model

Abstract

Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis and improved crypt proliferation. Donor cells expressed CD45 − , Sca-1 + , c-kit + , and CXCR4 + and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1 −/− mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.

Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease

“…SuperMApo stimulates wound healing via the pro-healing properties of fibroblasts and IEC. We did not study whether efferocytosis factors also promoted extra-intestinal bone marrow-derived cell recruitment to participate in wound healing, as observed in a recent study using a parabiosis chemical-induced colitis model ( 50 ). It has been shown that colonic fibroblasts are critically involved in tissue repair in the gastrointestinal tract ( 43 ).…”

Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis

“…The severity of radiation-induced enteritis was assessed by the degree of maintenance of the epithelial architecture, crypt damage, vascular enlargement, and infiltration of inflammatory cells in the lamina propria. This assessment is a modification of the histological score parameter used by Sung et al [ 29 ]. To perform immunohistochemical analysis, slides were subjected to antigen retrieval and then treated with 0.3% hydrogen peroxide in methyl alcohol for 20 min to block endogenous peroxidase activity.…”

Centella Asiatica Ameliorates Radiation-induced Epithelial Barrier Dysfunction by Secreting Epidermal Growth Factor in Endothelial Cells.

“…The severity of radiation-induced enteritis was assessed by the degree of maintenance of the epithelial architecture, crypt damage, vascular enlargement, and in ltration of in ammatory cells in the lamina propria. This assessment is a modi cation of the histological score parameter used by Sung et al [70]. To perform immunohistochemical analysis, slides were subjected to antigen retrieval and then treated with 0.3% hydrogen peroxide in methyl alcohol for 20 min to block endogenous peroxidase activity.…”