From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Circulation. 2014 Sep 9;130(11 Suppl 1):S70-6. doi: 10.1161/CIRCULATIONAHA.113.007908.
The impact of diabetes mellitus on the cardiac regenerative potential of cardiac stem cells (CSCs) is unknown yet critical, given that individuals with diabetes mellitus may well require CSC therapy in the future. Using human and murine CSCs from diabetic cardiac tissue, we tested the hypothesis that hyperglycemic conditions impair CSC function.
CSCs cultured from the cardiac biopsies of patients with diabetes mellitus (hemoglobin A1c, 10±2%) demonstrated reduced overall cell numbers compared with nondiabetic sourced biopsies (P=0.04). When injected into the infarct border zone of immunodeficient mice 1 week after myocardial infarction, CSCs from patients with diabetes mellitus demonstrated reduced cardiac repair compared with nondiabetic patients. Conditioned medium from CSCs of patients with diabetes mellitus displayed a reduced ability to promote in vitro blood vessel formation (P=0.02). Similarly, conditioned medium from CSCs cultured from the cardiac biopsies of streptozotocin-induced diabetic mice displayed impaired angiogenic capacity (P=0.0008). Somatic gene transfer of the methylglyoxal detoxification enzyme, glyoxalase-1, restored the angiogenic capacity of diabetic CSCs (diabetic transgenic versus nondiabetic transgenic; P=0.8). Culture of nondiabetic murine cardiac biopsies under high (25 mmol/L) glucose conditions reduced CSC yield (P=0.003), impaired angiogenic (P=0.02) and chemotactic (P=0.003) response, and reduced CSC-mediated cardiac repair (P<0.05).
Diabetes mellitus reduces the ability of CSCs to repair injured myocardium. Both diabetes mellitus and preconditioning CSCs in high glucose attenuated the proangiogenic capacity of CSCs. Increased expression of glyoxalase-1 restored the proangiogenic capacity of diabetic CSCs, suggesting a means of reversing diabetic CSC dysfunction by interfering with the accumulation of reactive dicarbonyls.
糖尿病对心脏干细胞（CSC）的心脏再生潜能的影响尚不清楚，但却很关键，因为未来患有糖尿病的个体很可能需要 CSC 治疗。本研究使用来自糖尿病心脏组织的人类和鼠类 CSC，检验了高血糖环境损害 CSC 功能这一假说。
与非糖尿病来源的活检组织相比，来自糖尿病患者心脏活检的 CSC 培养物显示整体细胞数量减少（P=0.04）。在心肌梗死 1 周后将 CSC 注射到免疫缺陷小鼠的梗死边缘区，来自糖尿病患者的 CSC 显示心脏修复能力较非糖尿病患者降低。糖尿病患者来源的 CSC 的条件培养基显示出促进体外血管形成的能力降低（P=0.02）。同样，来自链脲佐菌素诱导的糖尿病小鼠心脏活检的 CSC 培养物的条件培养基显示出受损的血管生成能力（P=0.0008）。过表达甲基乙二醛解毒酶，即甘油醛-3-磷酸脱氢酶-1，恢复了糖尿病 CSC 的血管生成能力（糖尿病转基因与非糖尿病转基因比较；P=0.8）。在高（25mmol/L）葡萄糖条件下培养非糖尿病鼠类心脏活检会降低 CSC 的产量（P=0.003），损害血管生成（P=0.02）和趋化（P=0.003）反应，并降低 CSC 介导的心脏修复（P<0.05）。
糖尿病降低了 CSC 修复受损心肌的能力。糖尿病和高糖预处理 CSC 均减弱了 CSC 的促血管生成能力。增加甘油醛-3-磷酸脱氢酶-1 的表达恢复了糖尿病 CSC 的促血管生成能力，这表明通过干扰反应性二羰基化合物的积累来逆转糖尿病 CSC 功能障碍的一种方法。
