MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF‐β1 levels

Abstract

Abstract Mutations in the CD18 gene encoding the common ?-chain of ?2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18?/? wounds by restoring the decreased TGF-?1 concentrations. TGF-?1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF-?1 concentrations at wound sites. Low TGF-?1 concentrations as occurring in CD18?/? wounds induce TGF-?1 release from MSCs, whereas high TGF-?1 concentrations suppress TGF-?1 production. This regulation depends on TGF-? receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-?1 signaling. Inactivation of TGF-? receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-?1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.