Diabetes Center of Excellence; Department of Surgery, Division of Vascular and Endovascular Surgery; Department of Molecular, Cell, and Cancer Biology
Cell Biology | Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Genetic Phenomena | Nutritional and Metabolic Diseases
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.
Diabetes complications, DNA methylation, Haematopoietic stem cells, Monocytes and macrophages
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© The Author(s) 2017. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Nat Commun. 2018 Jan 2;9(1):33. doi: 10.1038/s41467-017-02425-z. Link to article on publisher's site
Yan, Jinglian; Tie, Guodong; Wang, Shoying; Tutto, Amanda A.; DeMarco, Natale; Khair, Lyne; Fazzio, Thomas G.; and Messina, Louis M., "Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages" (2018). Open Access Articles. 3378.
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This work is licensed under a Creative Commons Attribution 4.0 License.
Cell Biology Commons, Cellular and Molecular Physiology Commons, Endocrine System Diseases Commons, Endocrinology Commons, Endocrinology, Diabetes, and Metabolism Commons, Genetic Phenomena Commons, Nutritional and Metabolic Diseases Commons