Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Department of Endocrinology, First Hospital of Harbin, Harbin, People's Republic of China.
Stem Cell Res Ther. 2022 Aug 13;13(1):418. doi: 10.1186/s13287-022-03099-1.
Autologous stem cell therapy is a promising strategy for cardiovascular diseases including diabetic cardiomyopathy (DCM), but conclusions from clinical trials were compromised. We assumed that diabetes might induce the dysfunction of stem cells and thus limit its therapeutic effect. This study aimed to compare the effect of diabetes and nondiabetes-derived bone marrow mesenchymal stem cells (BMSCs) transplantation on DCM and explored the potential mechanism.
Rats with diabetes were induced using high-fat diets and streptozotocin (STZ) injection. BMSCs harvested from diabetic and nondiabetic rats were infused into DCM rats, and the effects on the heart were identified by echocardiography and histopathology. The inhibition or overexpression of SAHH in nondiabetic and diabetic BMSCs was used to confirm its key role in stem cell activity and cardiac therapy.
Compared with normal BMSCs, the therapeutic effects of diabetic rat-derived stem cells on improving cardiac function and adverse remodeling were significantly attenuated. In vitro, diabetic BMSCs had lower cell viability and paracrine function than nondiabetic BMSCs. It was further found that diabetic BMSCs had obvious mitochondrial oxidative stress damage and S-adenosylhomocysteine (SAH) accumulation due to S-adenosylhomocysteine hydrolase (SAHH) deficiency. SAHH inhibition by adenosine dialdehyde (ADA) or shSAHH plasmid in normal BMSCs significantly reduced the favorable effects on endothelial cell proliferation and tube-forming capacity. In contrast, SAHH overexpression in diabetic BMSCs significantly improved cellular activity and paracrine function. Transplantation of BMSCs with SAHH overexpression improved cardiac adverse remodeling and angiogenesis. Activation of the Nrf2 signaling pathway may be one of the key mechanisms of SAHH-mediated improvement of stem cell viability and cardiac repair.
Diabetes leads to compromised bioactivity and repair capacity of BMSCs. Our study suggests that SAHH activation may improve the cardioprotective effect of autologous transplantation of diabetes-derived BMSCs on patients with DCM. Diabetes induced the inhibition of S-adenosylhomocysteine (SAH) expression and aging phenotype in BMSCs and thus decreased the cell viability and paracrine function. Compared with normal BMSCs, the therapeutic effects of diabetic rat-derived BMSCs on improving cardiac function and adverse remodeling were significantly attenuated. SAHH overexpression in diabetic BMSCs significantly rescued cellular function partly via activating Nrf2/HO-1 signal. Transplantation of diabetic BMSCs with SAHH overexpression improved angiogenesis and cardiac adverse remodeling in rats.
自体干细胞疗法是一种有前途的治疗策略，可用于治疗包括糖尿病心肌病（DCM）在内的心血管疾病，但临床试验的结论受到了影响。我们假设糖尿病可能导致干细胞功能障碍，从而限制其治疗效果。本研究旨在比较糖尿病和非糖尿病来源的骨髓间充质干细胞（BMSCs）移植对 DCM 的影响，并探讨其潜在机制。
使用高脂肪饮食和链脲佐菌素（STZ）注射诱导糖尿病大鼠。从糖尿病和非糖尿病大鼠中提取 BMSCs，然后将其输注到 DCM 大鼠中，通过超声心动图和组织病理学鉴定对心脏的影响。使用非糖尿病和糖尿病 BMSCs 中的 SAHH 抑制或过表达来确认其在干细胞活性和心脏治疗中的关键作用。
与正常 BMSCs 相比，糖尿病大鼠来源的干细胞改善心脏功能和不良重构的治疗效果明显减弱。体外实验表明，糖尿病 BMSCs 的细胞活力和旁分泌功能低于非糖尿病 BMSCs。进一步发现，由于 S-腺苷同型半胱氨酸水解酶（SAHH）缺乏，糖尿病 BMSCs 存在明显的线粒体氧化应激损伤和 S-腺苷高半胱氨酸（SAH）积累。用腺苷二醛（ADA）或 shSAHH 质粒抑制正常 BMSCs 中的 SAHH 显著降低了对内皮细胞增殖和管状形成能力的有利影响。相反，在糖尿病 BMSCs 中过表达 SAHH 可显著改善细胞活性和旁分泌功能。过表达 SAHH 的 BMSCs 移植可改善心脏不良重构和血管生成。Nrf2 信号通路的激活可能是 SAHH 介导改善干细胞活力和心脏修复的关键机制之一。
糖尿病导致 BMSCs 的生物活性和修复能力受损。我们的研究表明，SAHH 激活可能改善糖尿病患者自体移植糖尿病来源的 BMSCs 对 DCM 的心脏保护作用。糖尿病诱导 BMSCs 中 S-腺苷同型半胱氨酸（SAH）表达和衰老表型的抑制，从而降低细胞活力和旁分泌功能。与正常 BMSCs 相比，糖尿病大鼠来源的 BMSCs 改善心脏功能和不良重构的治疗效果明显减弱。过表达 SAHH 的糖尿病 BMSCs 部分通过激活 Nrf2/HO-1 信号来挽救细胞功能。过表达 SAHH 的糖尿病 BMSCs 移植可改善大鼠的血管生成和心脏不良重构。
