Research progress on the differentiation and apoptosis mechanisms of A9 dopaminergic neurons derived from stem cells and their regulation

Xujing Yang

doi:10.54254/3049-5458/2026.34047

Abstract

Current Parkinson's Disease (PD) treatments alleviate symptoms but do not halt progression from degeneration of A9 dopaminergic neurons in substantia nigra pars compacta. Human induced Pluripotent Stem Cells (iPSCs)-based cell replacement therapy has emerged as a promising therapy to PD, but it still faces two significant challenges. One of them is that it is difficult to generate sufficient high-purity and functional A9 neurons effectively; the other is that transplanted neurons readily perish in the hostile brain milieu, which significantly suppresses therapeutic actions. This review presents the fundamental molecular pathways regulating the differentiation of human iPSCs into A9-type dopaminergic neurons in a directional manner. It addresses the systematic control of Shh, Wnt/β-catenin, and SMAD signal transduction, and significant transcription factors such as FoxA2, Lmx1a/b, Nurr1, and Pitx3, a collective of which plays a crucial role in defining the distinct molecular attributes of the A9 neurons. Two practical and efficient differentiation protocols are summarized: a pretreatment system using three small molecules based on CTraS, and an optimized induction strategy targeting SHH/Wnt signaling pathways. Moreover, this review illustrates the fundamental mechanism of neuron apoptosis focusing on mitochondrial pathway and details two viable approaches to enhance the anti-apoptotic ability of A9 neurons via activating Nur77-PARL-BCL-2 signal pathway and enhancing expression of miR-221. Finally, the new concept of functionalization based on efficient differentiation and anti-apoptotic modification proposed in this review is expected to yield ideal high-yield, purity and survival robust A9 neurons. This review refers to theoretical delivery and clinical strategies for stimulating the use of iPSC-based PD cell therapy.

Keywords: Parkinson's disease , stem cell , A9 dopaminergic neuron , differentiation , apoptosis

Article Information

Received: 29 April 2026

Published: 29 May 2026

DOI: https://doi.org/10.54254/3049-5458/2026.34047

Article Type: Research Article

Cite this article

Yang,X. (2026). Research progress on the differentiation and apoptosis mechanisms of A9 dopaminergic neurons derived from stem cells and their regulation. Journal of Clinical Technology and Theory,4(3),132-139.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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Journal: Journal of Clinical Technology and Theory

Volume: Vol.4, Issue 3

ISSN: 3049-5458 (Print) / 3049-5466 (Online)

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[1]Szunyogh, S., Carroll, E., & Wade-Martins, R. (2025). Recent developments in gene therapy for Parkinson's disease.Molecular Therapy, 33(5), 2052–2064.

[2]Rahimi Darehbagh, R., Seyedoshohadaei, S. A., Ramezani, R., & Rezaei, N. (2024). Stem cell therapies for neurological disorders: Current progress, challenges, and future perspectives.European Journal of Medical Research, 29(1), 386.

[3]Chang, M. Y., & Lee, S. H. (2025). Human pluripotent stem cell-based therapies for Parkinson's disease: Challenges and potential solutions.Yonsei Medical Journal, 66(7), 395–404.

[4]Mishra, A. K., Dixit, S., Singh, A., Shukla, T., & Rizvi, S. I. (2025). Molecular determinants of A9 dopaminergic neurons.NeuromolecularMedicine, 27(1), 43.

[5]Kim, T. W., Piao, J., Bocchi, V. D., Koo, S. Y., Choi, S. J., Chaudhry, F., Yang, D., Cho, H. S., Hergenreder, E., Perera, L. R., Joshi, S., Mrad, Z. A., Claros, N., Donohue, S. A., Frank, A. K., Walsh, R., Mosharov, E. V., Betel, D., Tabar, V., & Studer, L. (2025). Enhanced yield and subtype identity of hPSC-derived midbrain dopamine neuron by modulation of WNT and FGF18 signaling. bioRxiv. https: //doi.org/10.1101/2025.01.06.631400

[6]Li, H., Jiang, H., Li, H., Li, L., Yan, Z., & Feng, J. (2022). Generation of human A9 dopaminergic pacemakers from induced pluripotent stem cells.Molecular Psychiatry, 27(11), 4407–4418.

[7]Jiang, C., Wan, X., He, Y., Pan, T., Jankovic, J., & Le, W. (2005). Age-dependent dopaminergic dysfunction in Nurr1 knockout mice.Experimental Neurology, 191(1), 154–162.

[8]Jacobs, F. M., van Erp, S., van der Linden, A. J., von Oerthel, L., Burbach, J. P., & Smidt, M. P. (2009). Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression.Development, 136(4), 531–540.

[9]Nakamura, R., Nonaka, R., Oyama, G., Jo, T., Kamo, H., Nuermaimaiti, M., Akamatsu, W., Ishikawa, K. I., & Hattori, N. (2023). A defined method for differentiating human iPSCs into midbrain dopaminergic progenitors that safely restore motor deficits in Parkinson's disease.Frontiers in Neuroscience, 17, 1202027.

[10]Dailah, H. G. (2022). Potential of therapeutic small molecules in apoptosis regulation in the treatment of neurodegenerative diseases: An updated review.Molecules, 27(21), 7207.

[11]Yin, S., Zhai, Y., Song, R., Wu, J., Zhang, Y., Yu, M., Ma, H., Shen, M., Lai, X., Jin, W., Xu, Y., & Yan, J. (2025). PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.Cell Death & Disease, 16(1), 700.

[12]Yao, Y., Zhao, Z., Zhang, F., Miao, N., Wang, N., Xu, X., & Yang, C. (2023). microRNA-221 rescues the loss of dopaminergic neurons in a mouse model of Parkinson's disease.Brain and Behavior, 13(3), e2921.