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

• Published in: EMBO reports 2020-04, Vol.21 (4), p.e49115-n/a
• Main Authors: Jiang, Dongsheng, Singh, Karmveer, Muschhammer, Jana, Schatz, Susanne, Sindrilaru, Anca, Makrantonaki, Evgenia, Qi, Yu, Wlaschek, Meinhard, Scharffetter‐Kochanek, Karin
• Format: Article
• Language: English
• Subjects: Adipose tissue; Animals; CD18 antigen; Cell Differentiation; chronic wounds; Contraction; Deactivation; Detection; Differentiation; EMBO24; EMBO37; EMBO38; environment sensing; Granulation; Inactivation; Integrins; LAD1; Leukocyte-Adhesion Deficiency Syndrome; Leukocytes; Levels; Mesenchymal Stem Cells; Mesenchyme; Mice; MicroRNAs; microRNA‐21; miRNA; Mutation; Receptors; Ribonucleic acid; RNA; Signaling; Smad7 protein; Stem cell transplantation; Stem cells; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b; Transforming growth factor-b1; Transplantation; Wound healing; Wound Healing - genetics
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201949115

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. Graphical 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.