Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models

Biochem Biophys Res Commun. 2020 Aug 13;529(1):7-14. doi: 10.1016/j.bbrc.2020.05.036. Epub 2020 Jun 5.

Abstract

This study aimed to investigate the role of truncated growth differentiation factor 11 (GDF11), in which the recognition site of Furin from wild-type GDF11 was deleted to enhance the cellular stability, in skin wound healing in the setting of diabetes mellitus (DM) and the underlying mechanisms. Our study found that both truncated and natural GDF11s effectively accelerated wound healing processes in both T1DM and T2DM mice with a potency compatible to PDGF, bFGF, and EGF, but being much higher than GDF8. At the cellular level, GDF11 stimulated the proliferation and suppressed HG-induced apoptosis of HSFs. Further study revealed that GDF11 activated the YAP-Smad2/3-CTGF fibrotic signaling pathway by reversing HG-induced upregulation of phosphorylated form of YAP (p-YAP), increases p-Smad2/3 levels, and restoring HG-induced repression of CTGF expression by GDF11. Overall, the study shows that both natural and truncated GDF11s promote the healing process of skin wound in mice of both T1DM and T2DM partly via stimulating dermal fibrosis via the YAP-Smad2/3-CTGF pathway, suggesting it a potential agent for treating skin wound in diabetic population.

Keywords: Diabetes mellitus; Fibrosis; Growth differentiation factor 11; High glucose; Hippo pathway; Skin wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Bone Morphogenetic Proteins / administration & dosage*
  • Bone Morphogenetic Proteins / physiology
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • Growth Differentiation Factors / administration & dosage*
  • Growth Differentiation Factors / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Skin / drug effects
  • Skin / injuries
  • Skin / pathology
  • Wound Healing / drug effects*
  • Wound Healing / physiology

Substances

  • Bone Morphogenetic Proteins
  • GDF11 protein, human
  • Gdf11 protein, mouse
  • Growth Differentiation Factors