Yang Jijuan, Li Chun, Wang Chunhua, Wang Xuemei, Liu Jiaqi, Yu Nan, Du Wenqing, Chi Shuhong
Department of Rheumatology, General Hospital of Ningxia Medical University, No. 804 Shengli South Street, Xingqing District, Yinchuan, 750004, China.
Bohai New Area, Beijing University of Chinese Medicine DongFang College, Cangzhou, 061108, China.
J Mol Neurosci. 2025 Jun 13;75(2):75. doi: 10.1007/s12031-025-02367-y.
Neuronal replacement therapy recently holds promise for neurodegenerative disease treatment. Somatic cell-derived neurons are the main cell source for this therapy; however, the induction mechanisms remain to be fully elucidated. Emerging evidence indicates that mitochondrial architecture undergoes substantial remodeling throughout cellular reprogramming processes. To explore the implications of mitochondrial dynamics in chemical-induced neuronal transdifferentiation, human foreskin fibroblasts (HFFs) were directly reprogrammed into functional neurons with our previously developed small molecule compound. The results showed that the mitochondrial morphology of HFFs shifted from tubular and reticular to fragmented shapes at an early stage of induced neurulation. Concurrently, gene and protein expression levels of the mitochondrial fission protein Drp1 was significantly increased in HFFs after induction. Both Drp1-specific siRNA and Drp1-GTPase inhibitor mdivi-1 treatment significantly attenuated the neuronal transdifferentiation of HFFs to neurons respectively, which can be attributed to the modulation of mitochondrial dynamics toward a fusion-dominant state through Drp1 suppression. Collectively, our experimental findings establish Drp1-dependent mitochondrial fission as a critical early requirement in the chemical reprogramming cascade that facilitates HFF transdifferentiation into neuronal lineages. Targeting Drp1 may enhance the efficiency of neuronal transdifferentiation, thereby providing sufficient therapeutically relevant neurons for neurodegenerative disease treatment.
神经元替代疗法最近在神经退行性疾病治疗方面展现出前景。体细胞衍生的神经元是这种疗法的主要细胞来源；然而，诱导机制仍有待充分阐明。新出现的证据表明，线粒体结构在整个细胞重编程过程中会经历显著重塑。为了探究线粒体动力学在化学诱导的神经元转分化中的作用，我们使用先前开发的小分子化合物将人包皮成纤维细胞（HFFs）直接重编程为功能性神经元。结果显示，在诱导神经形成的早期阶段，HFFs的线粒体形态从管状和网状转变为碎片状。同时，诱导后HFFs中线粒体分裂蛋白Drp1的基因和蛋白表达水平显著增加。Drp1特异性siRNA和Drp1 - GTPase抑制剂mdivi - 1处理分别显著减弱了HFFs向神经元的转分化，这可归因于通过抑制Drp1将线粒体动力学调节为融合主导状态。总体而言，我们的实验结果表明，依赖Drp1的线粒体分裂是化学重编程级联反应中的一个关键早期要求，该级联反应促进HFFs向神经元谱系的转分化。靶向Drp1可能会提高神经元转分化的效率，从而为神经退行性疾病治疗提供足够的具有治疗相关性的神经元。
