Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages

Nat Commun. 2018 Jan 2;9(1):33. doi: 10.1038/s41467-017-02425-z.

Abstract

People with type 2 diabetes mellitus (T2DM) have a 25-fold higher risk of limb loss than non-diabetics due in large part to impaired wound healing. Here, we show that the impaired wound healing phenotype found in T2D mice is recapitulated in lethally irradiated wild type recipients, whose hematopoiesis is reconstituted with hematopoietic stem cells (HSCs) from T2D mice, indicating an HSC-autonomous mechanism. This impaired wound healing phenotype of T2D mice is due to a Nox-2-dependent increase in HSC oxidant stress that decreases microRNA let-7d-3p, which, in turn, directly upregulates Dnmt1, leading to the hypermethylation of Notch1, PU.1, and Klf4. This HSC-autonomous mechanism reduces the number of wound macrophages and skews their polarization towards M1 macrophages. These findings reveal a novel inflammatory mechanism by which a metabolic disorder induces an epigenetic mechanism in HSCs, which predetermines the gene expression of terminally differentiated inflammatory cells that controls their number and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA Methylation
  • Diabetes Mellitus, Type 2 / metabolism*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Mice
  • MicroRNAs / genetics
  • NADPH Oxidase 2 / metabolism
  • Oxidative Stress
  • Proto-Oncogene Proteins / genetics
  • Receptor, Notch1 / genetics
  • Trans-Activators / genetics
  • Wound Healing / genetics*

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MicroRNAs
  • Notch1 protein, mouse
  • Proto-Oncogene Proteins
  • Receptor, Notch1
  • Trans-Activators
  • mirnlet7 microRNA, mouse
  • proto-oncogene protein Spi-1
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse