Glial cell line derived neurotrophic factor (GDNF) induces mucosal healing via intestinal stem cell niche activation

Abstract

Mucosal healing is critical to maintain and restore intestinal homeostasis in inflammation. Previous data provide evidence that glial cell line-derived neurotrophic factor (GDNF) restores epithelial integrity by largely undefined mechanisms. Here, we assessed the role of GDNF for mucosal healing. In dextran sodium sulphate (DSS)-induced colitis in mice application of GDNF enhanced recovery as revealed by reduced disease activity index and histological inflammation scores. In biopsy-based wounding experiments GDNF application in mice improved healing of the intestinal mucosa. GDNF-induced epithelial recovery was also evident in wound assays from intestinal organoids and Caco2 cells. These observations were accompanied by an increased number of Ki67-positive cells in vivo after GDNF treatment, which were present along elongated proliferative areas within the crypts. In addition, the intestinal stem cell marker and R-spondin receptor LGR5 was significantly upregulated following GDNF treatment in all experimental models. The effects of GDNF on cell proliferation, LGR5 and Ki67 upregulation were blocked using the RET-specific inhibitor BLU-667. Downstream of RET-phosphorylation, activation of Src kinase was involved to mediate GDNF effects. GDNF promotes intestinal wound healing by promoting cell proliferation. This is mediated by RET-dependent activation of Src kinase with consecutive LGR5 upregulation, indicating activation of the stem cell niche.