Ramos-Acevedo Rodrigo, Morato-Torres Carmen Alejandra, Padilla-Godínez Francisco J, Bernal-Conde Luis Daniel, Palomero-Rivero Marcela, Zafar Faria, Collazo-Navarrete Omar, Soto-Rojas Luis O, Schüle Birgitt, Guerra-Crespo Magdalena
Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Coyoacan, Mexico City 04510, Mexico.
Department of Molecular Neuropathology, Institute of Cell Physiology, National Autonomous University of Mexico, Coyoacan, Mexico City 04510, Mexico.
Brain Sci. 2023 Feb 14;13(2):329. doi: 10.3390/brainsci13020329.
Transplantation of immature dopaminergic neurons or neural precursors derived from embryonic stem cells (ESCs) into the substantia nigra pars compacta (SNpc) is a potential therapeutic approach for functional restitution of the nigrostriatal pathway in Parkinson's disease (PD). However, further studies are needed to understand the effects of the local microenvironment on the transplanted cells to improve survival and specific differentiation in situ. We have previously reported that the adult SNpc sustains a neurogenic microenvironment. Non-neuralized embryoid body cells (EBCs) from mouse ESCs (mESCs) overexpressing the dopaminergic transcription factor gave rise to many tyrosine hydroxylase (Th) cells in the intact and damaged adult SNpc, although only for a short-term period. Here, we extended our study by transplanting EBCs from genetically engineered naive human ESC (hESC), overexpressing the dopaminergic transcription factors , , and (hESC-LFO), in the SNpc. Unexpectedly, no graft survival was observed in wild-type hESC EBCs transplants, whereas hESC-LFO EBCs showed viability in the SNpc. Interestingly, neural rosettes, a developmental hallmark of neuroepithelial tissue, emerged at 7- and 15-days post-transplantation (dpt) from the hESC-LFO EBCs. Neural rosettes expressed specification dopaminergic markers (Lmx1a, Otx2), which gave rise to several Th cells at 30 dpt. Our results suggest that the SNpc enables the robust initiation of neural differentiation of transplanted human EBCs prompted to differentiate toward the midbrain dopaminergic phenotype.
将源自胚胎干细胞（ESC）的未成熟多巴胺能神经元或神经前体细胞移植到黑质致密部（SNpc）是帕金森病（PD）中黑质纹状体通路功能恢复的一种潜在治疗方法。然而，需要进一步研究以了解局部微环境对移植细胞的影响，从而提高其在原位的存活率和特异性分化。我们之前报道过成年SNpc维持着一种神经发生微环境。来自过表达多巴胺能转录因子的小鼠ESC（mESC）的非神经化胚状体细胞（EBC），在完整和受损的成年SNpc中产生了许多酪氨酸羟化酶（Th）细胞，尽管只是短期的。在此，我们通过将来自基因工程化的未分化人ESC（hESC）、过表达多巴胺能转录因子、和（hESC-LFO）的EBC移植到SNpc中来扩展我们的研究。出乎意料的是，在野生型hESC EBC移植中未观察到移植物存活，而hESC-LFO EBC在SNpc中显示出活力。有趣的是，在移植后7天和15天（dpt），来自hESC-LFO EBC的神经玫瑰花结出现了，这是神经上皮组织的一个发育标志。神经玫瑰花结表达特异性多巴胺能标记物（Lmx1a、Otx2），在30 dpt时产生了几个Th细胞。我们的结果表明，SNpc能够有力地启动移植的人EBC向中脑多巴胺能表型分化的神经分化过程。
