帕金森病 (PD) 是一种神经退行性疾病，其特征是黑质 (SN) 中多巴胺能神经元的变性。神经炎症反应的激活在 PD 中起着关键作用。间充质干细胞 (MSC) 已成为治疗各种神经损伤的一种有前途的治疗方法，但有关其在帕金森病中的应用的报道有限，且其潜在机制仍不清楚。我们研究了临床级缺氧预处理嗅粘膜 (hOM) 的作用)-MSCs对PD模型和患者神经功能恢复的影响，以及对PD小鼠模型的预防作用。为了评估 hOM-MSC 暴露引起的神经炎症反应和神经功能恢复的改善，我们采用单细胞 RNA 测序 (scRNA-seq)、高通量测序 (ATAC-seq) 与全长测序相结合的转座酶可及染色质分析转录组异构体测序（ISO-seq）和功能测定。此外，我们还介绍了参加一项 I 期首次人体临床试验的初始患者队列的研究结果，该试验评估了 hOM-MSC 椎管内移植对严重 PD 患者的安全性和有效性。一项功能测定表明，转化生长因子hOM-MSC 分泌的 -β1 (TGF-β1) 在调节多巴胺能神经元线粒体功能恢复中发挥着关键作用。这种效果是通过改善 SN 中的小胶质细胞免疫调节和自噬稳态来实现的，这与神经炎症反应密切相关。从机制上讲，暴露于 hOM-MSC 可以改善神经炎症和神经功能恢复，部分由 TGF-β1 通过激活间变性淋巴瘤激酶/磷脂酰肌醇 3-激酶/蛋白激酶 B (ALK/PI3K/Akt) 信号通路介导。小胶质细胞位于 PD 患者的 SN 中。此外，hOM-MSCs的椎管内移植改善了神经功能的恢复并调节了神经炎症反应，并且在PD患者中没有观察到任何不良反应。这些发现为TGF-β1参与介导hOM-MSCs的有益作用提供了令人信服的证据PD 神经功能恢复的研究hOM-MSCs 的治疗和预防可能是一种有前途且有效的 PD 神经保护策略。此外，TGF-β1 可单独使用或与 hOM-MSC 疗法联合用于治疗 PD。© 2024。作者。

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear.We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients.A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD.These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.© 2024. The Author(s).