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

Mutations in the CD18 gene encoding the common beta-chain of beta 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-beta 1 concentrations. TGF-beta 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-beta 1 concentrations at wound sites. Low TGF-beta 1 concentrations as occurring in CD18(-/-) wounds induce TGF-beta 1 release from MSCs, whereas high TGF-beta 1 concentrations suppress TGF-beta 1 production. This regulation depends on TGF-beta receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-beta 1 signaling. Inactivation of TGF-beta receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-beta 1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.