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TGF-β1 media a melhora da recuperação funcional neural promovida por células-tronco mesenquimais da mucosa olfativa pré-condicionadas por hipóxia em modelos e pacientes com doença de Parkinson

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    Department of Neurosurgery, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410000, China

    National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, China

Yi Zhuo123,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, China

Wen-Shui Li13,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410013, China

Wen Lu14,  
  • Affiliation：

    Department of Neurosurgery, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410000, China

Xuan Li2,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410013, China

Li-Te Ge14,  
  • Affiliation：

    NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China

Yan Huang5,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Qing-Tao Gao1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Yu-Jia Deng1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, China

Xin-Chen Jiang13,  
  • Affiliation：

    Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410013, China

Zi-Wei Lan4,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, China

Que Deng13,  
  • Affiliation：

    First Clinical Department of Changsha Medical University, Changsha 410219, China

Yong-Heng Chen6,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Yi Xiao1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Shuo Lu1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Feng Jiang1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Zuo Liu1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Li Hu1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Yu Liu1,  
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

Yu Ding1,  
  • Affiliation：

    Department of Neurosurgery, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410000, China

Zheng-Wen He2,  
  • role： Corresponding author通信作者
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

  • Email：Tandean20230515@163.com
  • Introduction：* Tandean20230515@163.com
De-An Tan1*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

  • Email：duanda1983@foxmail.com
  • Introduction：duanda1983@foxmail.com
Da Duan1*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Hunan Provincial Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha 410003, China

    National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, China

  • Email：lumingcs163@126.com
  • Introduction：lumingcs163@126.com
Ming Lu13*

Resumo

Background: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.Methods: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 firstin-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients.Results: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.Conclusions: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.

Palavras-chave

Parkinson’s disease (PD);Hypoxia-preconditioned;Olfactory mucosa mesenchymal stem cells (OM-MSCs);Transforming growth factor-β1 (TGF-β1);Microglia;PI3K/Akt signaling pathway;Immune regulation;Autophagy

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