School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.
Int J Mol Sci. 2021 Nov 9;22(22):12141. doi: 10.3390/ijms222212141.
Transplantation of exogenous dopaminergic (DA) neurons is an alternative strategy to replenish DA neurons that have lost along the course of Parkinson's disease (PD). From the perspective of ethical acceptation, the source limitations, and the intrinsic features of PD pathology, astrocytes (AS) and mesenchymal stem cells (MSCs) are the two promising candidates of DA induction. In the present study, we induced AS or MSCs primary culture by the combination of the classical transcription-factor cocktails Mash1, Lmx1a, and Nurr1 (MLN), the chemical cocktails (S/C/D), and the morphogens SHH, FGF8, and FGF2 (S/F8/F2); the efficiency of induction into DA neurons was further analyzed by using immunostaining against the DA neuronal markers. AS could be efficiently converted into the DA neurons in vitro by the transcriptional regulation of MLN, and the combination with S/C/D or S/F8/F2 further increased the conversion efficiency. In contrast, MSCs from umbilical cord (UC-MSCs) or adipose tissue (AD-MSCs) showed moderate TH immunoreactivity after the induction with S/F8/F2 instead of with MLN or S/C/D. Our data demonstrated that AS and MSCs held lineage-specific molecular codes on the induction into DA neurons and highlighted the unique superiority of AS in the potential of cell replacement therapy for PD.
移植外源性多巴胺能(DA)神经元是一种替代策略,可以补充帕金森病(PD)过程中丢失的 DA 神经元。从伦理可接受性、来源限制和 PD 病理学的固有特征来看,星形胶质细胞(AS)和间充质干细胞(MSCs)是两种有前途的 DA 诱导候选物。在本研究中,我们通过经典转录因子鸡尾酒 Mash1、Lmx1a 和 Nurr1(MLN)、化学鸡尾酒(S/C/D)和形态发生素 SHH、FGF8 和 FGF2(S/F8/F2)组合,诱导 AS 或 MSC 原代培养;通过对 DA 神经元标志物的免疫染色进一步分析诱导为 DA 神经元的效率。通过 MLN 的转录调控,AS 可以在体外有效地转化为 DA 神经元,并且与 S/C/D 或 S/F8/F2 的组合进一步提高了转化效率。相比之下,脐带(UC-MSCs)或脂肪组织(AD-MSCs)来源的 MSC 在 S/F8/F2 诱导下而非 MLN 或 S/C/D 诱导下表现出中等 TH 免疫反应性。我们的数据表明,AS 和 MSCs 在诱导为 DA 神经元方面具有谱系特异性分子编码,并突出了 AS 在 PD 细胞替代治疗中的独特优势。