First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, No. 10 Changjiang Branch Road, Daping Street, Yuzhong District, Chongqing, 400042, People's Republic of China.
Department of Histology and Embryology, Medical College of Qingdao University, Qingdao, People's Republic of China.
Diabetologia. 2017 Sep;60(9):1822-1833. doi: 10.1007/s00125-017-4316-1. Epub 2017 Jun 3.
AIMS/HYPOTHESIS: Regeneration and repair mediated by mesenchymal stem cells (MSCs) are key self-protection mechanisms against diabetic complications, a reflection of diabetes-related cell/tissue damage and dysfunction. MSC abnormalities have been reported during the progression of diabetic complications, but little is known about whether a deficiency in these cells plays a role in the pathogenesis of this disease. In addition to MSC resident sites, peripheral circulation is a major source of MSCs that participate in the regeneration and repair of damaged tissue. Therefore, we investigated whether there is a deficiency of circulating MSC-like cells in people with diabetes and explored the underlying mechanisms.
The abundance of MSC-like cells in peripheral blood was evaluated by FACS. Selected diabetic and non-diabetic serum (DS and NDS, respectively) samples were used to mimic diabetic and non-diabetic microenvironments, respectively. The proliferation and survival of MSCs under different serum conditions were analysed using several detection methods. The survival of MSCs in diabetic microenvironments was also investigated in vivo using leptin receptor mutant (Lepr ) mice.
Our data showed a significant decrease in the abundance of circulating MSC-like cells, which was correlated with complications in individuals with type 2 diabetes. DS strongly impaired the proliferation and survival of culture-expanded MSCs through the complement system but not through exposure to high glucose levels. DS-induced MSC apoptosis was mediated, at least in part, by the complement C5a-dependent upregulation of Fas-associated protein with death domain (FADD) and the Bcl-2-associated X protein (BAX)/B cell lymphoma 2 (Bcl-2) ratio, which was significantly inhibited by neutralising C5a or by the pharmacological or genetic inhibition of the C5a receptor (C5aR) on MSCs. Moreover, blockade of the C5a/C5aR pathway significantly inhibited the apoptosis of transplanted MSCs in Lepr recipient mice.
CONCLUSIONS/INTERPRETATION: C5a-dependent apoptotic death is probably involved in MSC deficiency and in the progression of complications in individuals with type 2 diabetes. Therefore, anticomplement therapy may be a novel intervention for diabetic complications.
目的/假设：间充质干细胞（MSCs）介导的再生和修复是对抗糖尿病并发症的关键自我保护机制，这反映了与糖尿病相关的细胞/组织损伤和功能障碍。在糖尿病并发症的进展过程中，已经报道了 MSC 的异常，但尚不清楚这些细胞的缺乏是否在该疾病的发病机制中起作用。除了 MSC 驻留部位外，外周循环是参与损伤组织再生和修复的 MSC 的主要来源。因此，我们研究了糖尿病患者外周循环中是否存在 MSC 样细胞缺乏，并探讨了其潜在机制。
通过 FACS 评估外周血 MSC 样细胞的丰度。选择糖尿病和非糖尿病血清（DS 和 NDS，分别）样本分别模拟糖尿病和非糖尿病微环境。使用几种检测方法分析了不同血清条件下 MSC 的增殖和存活。还使用瘦素受体突变（Lepr ）小鼠在体内研究了 MSC 在糖尿病微环境中的存活。
我们的数据显示，循环 MSC 样细胞的丰度显著减少，这与 2 型糖尿病个体的并发症相关。DS 通过补体系统而非暴露于高葡萄糖水平强烈损害培养扩增 MSC 的增殖和存活。DS 诱导的 MSC 凋亡至少部分是通过补体 C5a 依赖性 Fas 相关死亡结构域（FADD）和 B 细胞淋巴瘤 2（Bcl-2）相关 X 蛋白（BAX）/Bcl-2 比值的上调介导的，这可以通过中和 C5a 或通过 MSC 上 C5a 受体（C5aR）的药理学或遗传抑制来显著抑制。此外，阻断 C5a/C5aR 途径可显著抑制 Lepr 受体小鼠中移植 MSC 的凋亡。
结论/解释：C5a 依赖性凋亡可能参与了 2 型糖尿病患者 MSC 缺乏和并发症进展。因此，抗补体治疗可能是治疗糖尿病并发症的一种新方法。
