Yan Jinglian, Tie Guodong, Wang Shouying, Tutto Amanda, DeMarco Natale, Khair Lyne, Fazzio Thomas G, Messina Louis M
Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
Nat Commun. 2018 Jan 2;9(1):33. doi: 10.1038/s41467-017-02425-z.
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.
2型糖尿病（T2DM）患者肢体丧失的风险比非糖尿病患者高25倍，这在很大程度上归因于伤口愈合受损。在此，我们表明，在接受致死性照射的野生型受体中再现了T2D小鼠中发现的伤口愈合受损表型，这些受体的造血功能由来自T2D小鼠的造血干细胞（HSC）重建，这表明存在一种HSC自主机制。T2D小鼠的这种伤口愈合受损表型是由于HSC氧化应激的Nox-2依赖性增加，这会降低微小RNA let-7d-3p，进而直接上调Dnmt1，导致Notch1、PU.1和Klf4的高甲基化。这种HSC自主机制减少了伤口巨噬细胞的数量，并使它们的极化偏向M1巨噬细胞。这些发现揭示了一种新的炎症机制，即代谢紊乱在HSC中诱导一种表观遗传机制，该机制预先决定终末分化炎症细胞的基因表达，从而控制它们的数量和功能。
