Epigenetic changes can alter stem cells and wound healing in diabetes

Thanks to our SALSAmigo, Cuba/CIGB’s Jorge Berlanga Acosta for this great find from Gallagher and coworkers. Perhaps it is not only nature– but nurture that can influence healing!?

Diabetes. 2015 Apr;64(4):1420-30. doi: 10.2337/db14-0872. Epub 2014 Nov 3.

Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.

Gallagher KA1, Joshi A2, Carson WF3, Schaller M3, Allen R3, Mukerjee S3, Kittan N3, Feldman EL4, Henke PK2,Hogaboam C5, Burant CF6, Kunkel SL3.

Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically “preprogrammed” macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL-12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds

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