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Complement C5a induces mesenchymal stem cell apoptosis during the progression of chronic diabetic complications
Ming Zhu1, Xiao He1, Xiao-Hui Wang1,2
1First 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.
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.
Insights
Mesenchymal stem cells (MSCs) are deficient in type 2 diabetes, leading to complications. Complement C5a pathway activation causes MSC apoptosis, suggesting anticomplement therapy as a potential treatment.
Area of Science:
- Immunology
- Stem Cell Biology
- Endocrinology
Background:
- Mesenchymal stem cells (MSCs) are crucial for tissue repair and protecting against diabetic complications.
- Abnormalities in MSCs are observed in diabetes, but their role in disease pathogenesis is unclear.
- Circulating MSCs are vital for tissue regeneration, making their status in diabetes a key research question.
Purpose of the Study:
- To investigate the deficiency of circulating MSC-like cells in individuals with type 2 diabetes.
- To explore the mechanisms underlying MSC abnormalities in a diabetic microenvironment.
Main Methods:
- Flow cytometry (FACS) was used to quantify MSC-like cells in peripheral blood.
- Diabetic and non-diabetic sera were used to simulate different microenvironments for MSC culture.
- In vivo studies utilized leptin receptor mutant (Leprdb/db) mice to assess MSC survival in diabetic conditions.
Main Results:
- A significant reduction in circulating MSC-like cells was observed in type 2 diabetes patients, correlating with disease complications.
- Diabetic serum impaired MSC proliferation and survival, primarily via the complement system, not high glucose.
- MSC apoptosis was linked to complement C5a, FADD upregulation, and altered BAX/Bcl-2 ratio, which was reversed by C5a pathway inhibition.
Conclusions:
- C5a-dependent apoptosis contributes to MSC deficiency and diabetic complication progression.
- Targeting the C5a/C5aR pathway may offer a novel therapeutic strategy for diabetic complications.
- Anticomplement therapy presents a potential intervention for managing diabetes-related issues.
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