MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF‐β1 levels. (21st February 2020)

• Record Type: Journal Article
• Authors: Jiang, Dongsheng; Singh, Karmveer; Muschhammer, Jana; Schatz, Susanne; Sindrilaru, Anca; Makrantonaki, Evgenia; Qi, Yu; Wlaschek, Meinhard; Scharffetter‐Kochanek, Karin
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-21
• Subjects: chronic wounds -- environment sensing -- LAD1 -- mesenchymal stem cells -- microRNA‐21; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949115
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Mutations in the CD18 gene encoding the common β‐chain of β2 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‐β1 concentrations. TGF‐β1 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‐β1 concentrations at wound sites. Low TGF‐β1 concentrations as occurring in CD18 −/− wounds induce TGF‐β1 release from MSCs, whereas high TGF‐β1 concentrations suppress TGF‐β1 production. This regulation depends on TGF‐β receptor sensing and is relayed to microRNA‐21 (miR‐21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF‐β1 signaling. Inactivation of TGF‐β receptor, or overexpression or silencing of miR‐21 or Smad7, abrogates TGF‐β1 sensing, and thus prevents the adaptive MSC responses required for tissue repair. Synopsis: Mesenchymal stem cells accelerate wound healing in CD18 −/− mice by releasing TGF‐β1 in an environmental‐adaptive manner. The sensing of environmental TGF‐β1 level is mediated by TGF‐β receptor/microRNA‐21/Smad7 signaling. MSCs restore wound healing defects in CD18 −/− mice. MSC‐derived TGF‐β1 induces myofibroblast differentiation and restores granulation tissue formation in CD18 −/− wounds. MSCs regulate TGF‐β1 release by sensing environmental TGF‐β1 levels. TGF‐β1 sensing is mediated by TGF‐β receptor, microRNA‐21 and Smad7. Abstract : Mesenchymal stem cells accelerate wound healing in CD18 −/− mice by releasing TGF‐β1 in an environmental‐adaptive manner. The sensing of environmental TGF‐β1 level is mediated by TGF‐β receptor/microRNA‐21/Smad7 signaling.