Venetian Institute of Molecular Medicine, Padova, Italy.
Diabetes. 2014 Apr;63(4):1353-65. doi: 10.2337/db13-0894. Epub 2013 Nov 22.
Diabetes compromises the bone marrow (BM) microenvironment and reduces the number of circulating CD34(+) cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after ischemia in patients with diabetes. We report that, in patients, cardiovascular DAN was associated with fewer circulating CD34(+) cells. Experimental diabetes (streptozotocin-induced and ob/ob mice) or chemical sympathectomy in mice resulted in BM autonomic neuropathy, impaired Lin(-)cKit(+)Sca1(+) (LKS) cell and endothelial progenitor cell (EPC; CD34(+)Flk1(+)) mobilization, and vascular recovery after ischemia. DAN increased the expression of the 66-kDa protein from the src homology and collagen homology domain (p66Shc) and reduced the expression of sirtuin 1 (Sirt1) in mice and humans. p66Shc knockout (KO) in diabetic mice prevented DAN in the BM, and rescued defective LKS cell and EPC mobilization. Hematopoietic Sirt1 KO mimicked the diabetic mobilization defect, whereas hematopoietic Sirt1 overexpression in diabetes rescued defective mobilization and vascular repair. Through p66Shc and Sirt1, diabetes and sympathectomy elevated the expression of various adhesion molecules, including CD62L. CD62L KO partially rescued the defective stem/progenitor cell mobilization. In conclusion, autonomic neuropathy in the BM impairs stem cell mobilization in diabetes with dysregulation of the life-span regulators p66Shc and Sirt1.
糖尿病会损害骨髓（BM）微环境并减少循环 CD34(+)细胞的数量。糖尿病自主神经病变（DAN）可能会影响 BM，因为交感神经系统在 BM 干细胞迁移中起着重要作用。我们假设 BM 神经病变会影响糖尿病患者缺血后的干细胞动员和血管恢复。我们报告称，在患者中，心血管 DAN 与循环 CD34(+)细胞数量减少有关。实验性糖尿病（链脲佐菌素诱导和 ob/ob 小鼠）或小鼠的化学性交感神经切除术导致 BM 自主神经病变，损害 Lin(-)cKit(+)Sca1(+)（LKS）细胞和内皮祖细胞（EPC；CD34(+)Flk1(+)）动员以及缺血后的血管恢复。DAN 增加了 src 同源和胶原同源结构域（p66Shc）的 66 kDa 蛋白的表达，并降低了小鼠和人类中的 Sirtuin 1（Sirt1）的表达。糖尿病小鼠中的 p66Shc 敲除（KO）可防止 DAN 在 BM 中发生，并挽救了 LKS 细胞和 EPC 动员的缺陷。造血 Sirt1 KO 模拟了糖尿病动员缺陷，而糖尿病中造血 Sirt1 的过表达则挽救了动员缺陷和血管修复。通过 p66Shc 和 Sirt1，糖尿病和交感神经切除术提高了各种粘附分子的表达，包括 CD62L。CD62L KO 部分挽救了缺陷性干细胞/祖细胞动员。总之，BM 中的自主神经病变会损害糖尿病中的干细胞动员，其调节寿命调节剂 p66Shc 和 Sirt1 的失调。
