Abstract
CD47 is a ubiquitously expressed transmembrane glycoprotein that regulates inflammatory responses and tissue repair. Here, we show that normal mice treated with anti-CD47 antibodies, and Cd47-null mice have impaired intestinal mucosal wound healing. Furthermore, intestinal epithelial cell (IEC)-specific loss of CD47 does not induce spontaneous immune-mediated intestinal barrier disruption but results in defective mucosal repair after biopsy-induced colonic wounding or Dextran Sulfate Sodium (DSS)-induced mucosal damage. In vitro analyses using primary cultures of CD47-deficient murine colonic IEC or human colonoid-derived IEC treated with CD47-blocking antibodies demonstrate impaired epithelial cell migration in wound healing assays. Defective wound repair after CD47 loss is linked to decreased epithelial β1 integrin and focal adhesion signaling, as well as reduced thrombospondin-1 and TGF-β1. These results demonstrate a critical role for IEC-expressed CD47 in regulating mucosal repair and raise important considerations for possible alterations in wound healing secondary to therapeutic targeting of CD47.
Highlights
CD47 is a ubiquitously expressed transmembrane glycoprotein that regulates inflammatory responses and tissue repair
We further demonstrate a critical role of epithelial expressed CD47, as mice selectively deficient in intestinal epithelial cell (IEC) CD47 expression did not display abnormalities under resting conditions but exhibited profound defects in closure of biopsy-induced mucosal wounds as well as markedly impaired colonic mucosal wound repair from cyclic exposure to dextran sodium sulfate (DSS)-induced injury
Using two-dimensional (2D) cultures of primary epithelial cells derived from murine and human intestine, it was determined that CD47 regulates epithelial cell migration and wound closure through β1 integrin-dependent signaling through Focal adhesion kinase (FAK), Src protein-tyrosine kinase, and Crk-associated substrate p130Cas (p130Cas), thereby controlling the formation of focal cell matrix adhesions
Summary
CD47 is a ubiquitously expressed transmembrane glycoprotein that regulates inflammatory responses and tissue repair. Defective wound repair after CD47 loss is linked to decreased epithelial β1 integrin and focal adhesion signaling, as well as reduced thrombospondin-1 and TGF-β1 These results demonstrate a critical role for IEC-expressed CD47 in regulating mucosal repair and raise important considerations for possible alterations in wound healing secondary to therapeutic targeting of CD47. We corroborate evidence of crosstalk between CD47, β1 integrin, and focal adhesions as well as a functional link between CD47, TSP-1, and TGF-β1 in the intestinal epithelium These findings provide insights into a central role of CD47 in regulating IEC migration and mucosal wound repair in vivo, and raise the possibility of altered wound healing as a potential complication in clinical studies exploring blockade of CD47 to enhance clearance of CD47-overexpressing tumor cells in humans
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