Ming Zhu1, Xiao He1, Xiao-Hui Wang1,2, Wei Qiu1, Wei Xing1, Wei Guo1, Tian-Chen An1, Luo-Quan Ao1, Xue-Ting Hu1, Zhan Li1, Xiao-Ping Liu2, Nan Xiao3, Jian Yu4,5, Hong Huang6, Xiang Xu7. 1. 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. 2. Department of Histology and Embryology, Medical College of Qingdao University, Qingdao, People's Republic of China. 3. Ninth Department, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China. 4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 5. University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 6. 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. huanghongcq@163.com. 7. 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. xiangxu@ymail.com.
Abstract
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. METHODS: 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 db/db ) mice. RESULTS: 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 db/db 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.
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. METHODS: 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 db/db ) mice. RESULTS: 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 db/db 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.
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