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

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.

• Authors: Dongsheng Jiang, Karmveer Singh, Jana Muschhammer, Susanne Schatz, Anca Sindrilaru, Evgenia Makrantonaki, Yu Qi, Meinhard Wlaschek, Karin Scharffetter-Kochanek
• Journal: EMBO reports (EMBO Rep) Vol. 21 Issue 4 Pg. e49115 (04 03 2020) ISSN: 1469-3178 [Electronic] England
• PMID: 32080965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Transforming Growth Factor beta1

Topics

• Animals
• Cell Differentiation
• Leukocyte-Adhesion Deficiency Syndrome
• Mesenchymal Stem Cells
• Mice
• Transforming Growth Factor beta1 (genetics)
• Wound Healing (genetics)