Department of Geriatrics, The Second Affiliated Hospital, Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 210011, China; Department of Neurology, The Second People's Hospital of NanTong, Nantong 226006, China.
Department of Geriatrics, The Second Affiliated Hospital, Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 210011, China; Department of Neurology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China.
Mol Cell Neurosci. 2022 Dec;123:103784. doi: 10.1016/j.mcn.2022.103784. Epub 2022 Oct 11.
Parkinson's disease (PD) is a neurodegenerative disease still without any cure. Brain-derived neurotrophic factor (BDNF) has shown therapeutic potential in PD, which is limited by its short half-life and inability to penetrate the blood-brain barrier. Stem cells not only present migration, differentiation and neurotrophy characteristics, but also can be used as delivery vectors for BDNF. This study aimed to investigate the therapeutic effects and possible mechanisms of BDNF-modified human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived dopaminergic (DAergic)-like neurons in the PD rats. Results showed that transplantation of BDNF-modified hUC-MSCs-derived DAergic-like neurons improved the apomorphine induced rotation behavior of PD rats, increased the dopamine concentration and the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1) in the striatum, promoted the expression of tyrosine hydroxylase (TH), nuclear receptor-related factor 1 (Nurr1), pituitary homeobox 3 (Pitx3), BDNF, tyrosine kinase B (TrkB), phosphatidylinositol-3-hydroxykinase (PI3K), phosphorylated protein kinase B (p-Akt), heat shock protein 60 (Hsp60), toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) and inhibited the neural apoptosis in the substantia nigra (SN) and striatum. Results suggest that BDNF-modified hUC-MSCs-derived DAergic-like neurons improve the rotation of PD rats might through neuroprotection and anti-neuroinflammation by regulating the BDNF-TrkB-PI3K/Akt and Hsp60-TLR4/MyD88 signaling pathways, respectively.
帕金森病（PD）是一种尚无治愈方法的神经退行性疾病。脑源性神经营养因子（BDNF）在 PD 中显示出治疗潜力，但由于其半衰期短且无法穿透血脑屏障而受到限制。干细胞不仅具有迁移、分化和神经营养特性，还可以作为 BDNF 的递送载体。本研究旨在探讨 BDNF 修饰的人脐带间充质干细胞（hUC-MSCs）衍生的多巴胺能（DAergic）样神经元在 PD 大鼠中的治疗作用及可能机制。结果表明，移植 BDNF 修饰的 hUC-MSCs 衍生的 DAergic 样神经元改善了 PD 大鼠的阿扑吗啡诱导的旋转行为，增加了纹状体中的多巴胺浓度和神经胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子-1（Iba-1）的表达，促进了酪氨酸羟化酶（TH）、核受体相关因子 1（Nurr1）、垂体同源盒 3（Pitx3）、BDNF、酪氨酸激酶 B（TrkB）、磷酸肌醇-3-羟激酶（PI3K）、磷酸化蛋白激酶 B（p-Akt）、热休克蛋白 60（Hsp60）、Toll 样受体 4（TLR4）和髓样分化因子 88（MyD88）的表达，并抑制了黑质（SN）和纹状体中的神经凋亡。结果表明，BDNF 修饰的 hUC-MSCs 衍生的 DAergic 样神经元改善 PD 大鼠的旋转可能通过调节 BDNF-TrkB-PI3K/Akt 和 Hsp60-TLR4/MyD88 信号通路分别通过神经保护和抗神经炎症作用。
