National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China.
Mol Neurobiol. 2022 Nov;59(11):6666-6683. doi: 10.1007/s12035-022-03002-2. Epub 2022 Aug 20.
The purpose of this study is to explore the effect and mechanism of neuritin overexpression in the bone marrow on peripheral neuropathy in type 2 diabetic (db/db) mice. We analyzed the impact of bone marrow neuritin overexpression on diabetic peripheral neuropathy and migration of bone marrow mesenchymal stem cells in db/db mice. Antagonists were used to inhibit the stromal cell-derived factor (SDF)-1α/C-X-C chemokine receptor type 4 (CXCR4)-phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in primary cultured bone marrow mesenchymal stem cells. Immunofluorescence, transmission electron microscopy, Oil Red O staining, and transwell migration assays were used. Bone marrow-specific overexpression of neuritin in db/db mice was successfully established. Overexpression of neuritin in the bone marrow ameliorated hyperglycemia, prevented diabetic peripheral neuropathy, protected the ultrastructure of the sciatic nerve and intra-epidermal nerve fiber density, and promoted Schwann cell proliferation and remyelination in the sciatic nerve. Moreover, it ameliorated fat accumulation, adipocyte number, and vascular and nerve densities; decreased glutamate content in serum and bone marrow; restored gradient SDF-1α contents between bone marrow, blood, and sciatic nerve; and promoted impaired diabetic bone marrow mesenchymal stem cell migration. Neuritin improves bone marrow mesenchymal stem cell migration via the SDF-1α/CXCR4-PI3K/Akt signaling pathway in vitro. Overexpression of neuritin in the bone marrow can locally ameliorate neuropathy in the bone marrow. This improves the migration capability of bone marrow mesenchymal stem cells and repairs diabetic peripheral neuropathy, at least partly by activating the PI3K/Akt pathway through the SDF-1α/CXCR4 axis.
本研究旨在探讨骨髓中神经黏附素过表达对 2 型糖尿病（db/db）小鼠周围神经病变的作用及其机制。我们分析了骨髓中神经黏附素过表达对 db/db 小鼠糖尿病周围神经病变和骨髓间充质干细胞迁移的影响。使用拮抗剂抑制基质细胞衍生因子（SDF）-1α/C-X-C 趋化因子受体 4（CXCR4）-磷酸肌醇 3-激酶（PI3K）/Akt 信号通路在原代培养的骨髓间充质干细胞中。采用免疫荧光、透射电镜、油红 O 染色和 Transwell 迁移实验进行分析。成功建立了 db/db 小鼠骨髓中神经黏附素的特异性过表达模型。骨髓中神经黏附素的过表达改善了高血糖，预防了糖尿病周围神经病变，保护了坐骨神经的超微结构和表皮内神经纤维密度，并促进了坐骨神经中施万细胞的增殖和髓鞘形成。此外，它改善了脂肪堆积、脂肪细胞数量、血管和神经密度；降低了血清和骨髓中谷氨酸含量；恢复了骨髓、血液和坐骨神经之间 SDF-1α 含量的梯度；并促进了受损的糖尿病骨髓间充质干细胞的迁移。神经黏附素通过 SDF-1α/CXCR4-PI3K/Akt 信号通路在体外改善了骨髓间充质干细胞的迁移。骨髓中神经黏附素的过表达可以局部改善骨髓中的神经病变。这提高了骨髓间充质干细胞的迁移能力，并修复了糖尿病周围神经病变，至少部分通过激活 SDF-1α/CXCR4 轴上的 PI3K/Akt 通路来实现。
