Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation.
Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation.
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DOI：
10.1186/s13287-018-1020-0
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发表时间：
2018-10-25
影响因子：
7.5
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Zhang X;Qin J;Wang X;Guo X;Liu J;Wang X;Wu X;Lu X;Li W;Liu X
糖尿病周围神经血管病变(DPNvs)复杂，缺乏有效的治疗方法。脂肪干细胞(ADSCs)的自体/异基因移植是治疗DPNvs的一种很有前途的策略。然而，移植的ADSCs在体内的活性、迁移、黏附和分化能力都不理想，从而降低了治疗效率。Netrin-1作为轴突导向分子分泌，并作为血管生成因子，显示其在促进细胞增殖、迁移、黏附和新生血管形成方面的能力。用腺病毒方法(N-ADSCs)将Netrin-1基因(NTN-1)修饰脂肪组织中的ADSCs，并在高糖条件下检测细胞的增殖、迁移、黏附和凋亡。将N-ADSCs移植到2型糖尿病(T2 DM)失神经小鼠(db/db)的坐骨神经中，通过激光多普勒血流指数、免疫荧光和组织病理学方法评价其治疗效果。此外，还探讨了Netrin-1介导的ADSCs增殖、迁移、黏附、分化、促血管生成能力和凋亡的分子机制。N-ADSCs在高糖条件下促进体外培养的ADSCs的增殖、迁移和黏附，抑制细胞的凋亡。N-ADSCs组和对照组的激光多普勒血流灌注指数升高。N-ADSCs免疫荧光和组织病理学染色显示，移植肢体肌肉内有细胞分布，提示慢性缺血；N-ADSCs分化形成毛细血管和内皮。N-ADSCs组的微血管密度明显高于ADSCs组。AKT/PI3K/eNOS/P-38/NF-κB信号通路的上调和多种生长因子的分泌可能解释了Netrin-1对ADSCs的积极作用。Netrin-1在ADSCs中的过表达改善了2型糖尿病失神经小鼠的增殖、迁移和治疗效果，指导了DPNvs患者的临床治疗。
Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization. ADSCs acquired from adipose tissue were modified by Netrin-1 gene (NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored. N-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. The N-ADSCs group showed a significantly high density of the microvessels than the ADSCs group. The upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways and secretion of multiple growth factors might explain the positive effects of Netrin-1 on ADSCs. The overexpression of Netrin-1 in ADSCs improves proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation, which directs the clinical treatment of patients with DPNVs.
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