Abstract 199: Type 2 Diabetes Impairs Wound Healing By DNMT1-dependent Reduction of Hematopoietic Stem Cell Differentiation towards Monocytes/Macrophages and Skewing of the M1/M2 Polarization
Rationale: People with Type 2 Diabetes Mellitus (T2DM) have a 25x higher risk of limb loss than non-diabetics due in large part to impaired wound healing. The mechanisms that cause impaired wound healing remain incompletely characterized.
Objective: We hypothesize that T2DM impairs wound healing by epigenetic modifications in hematopoietic stem cells (HSC) that reduce their differentiation towards monocytes/macrophages and disrupts the balance in M1/M2 polarization during the three phases of wound healing.
Methods and Results: Wounds were created on the back of mice. Wound healing was significantly slower in diabetic db/db than in WT mice. During the early inflammatory phase, db/db wounds exhibited a significant decrease in total macrophages and M1 macrophages. Then, total macrophages and M2 macrophages were decreased, while M1 macrophages increased in tissue formation phase. In the late tissue remodeling phase, total macrophages and M1 macrophages were persistently increased. The impaired wound healing phenotype of db/db mice was recapitulated in WT recipients which were resconstituted with db/db HSCs, demonstrating that the impaired differentiation of HSCs towards macrophages as well as their M1/M2 polarization was due to a cell autonomous mechanism. Epigenetic studies indicated that DNMT1-dependent hypermethylation of Notch1, Pu.1 and KLF4 in T2D HSCs was responsible for the impaired differentiation towards monocytes/macrophages as well as the skewed M1/M2 polarization. Knockdown of DNMT1 in HSCs from db/db mice transplanted into lethally irradiated WT mice led to improved wound healing by an increase in macrophage infiltration as well as a normalization of the M1/M2 polarization.
Conclusion: This study indicates that the dynamic changes of macrophage concentration and M1/M2 polarization in wound healing are regulated at the level of HSCs. Moreover, T2DM impairs wound healing by inducing DNMT1-dependent reduction of HSCs’ differentiation towards macrophages and their M1/M2 polarization. This novel finding indicates that inflammation is regulated at the level of HSCs, which creates new opportunities to develop epigenetic modification related therapies for T2DM and potentially other conditions that result from dysinflammation.
Author Disclosures: J. Yan: None. G. Tie: None. L. Khair: None. E. Filippova: None. L. Messina: None.
- © 2015 by American Heart Association, Inc.