Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.140
Efficient Generation of Dopaminergic Neurons from Mouse Ventral Midbrain Astrocytes
Jin Yi Han1, Eun-Hye Lee2,3, Sang-Mi Kim4,5 and Chang-Hwan Park1,4,6,*
1Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
2Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205,
3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763,
5Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488,
6Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
*E-mail: chshpark@hanyang.ac.kr
Tel: +82-2-2220-0646, Fax: +82-2-2220-2422
Received: November 5, 2022; Revised: December 9, 2022; Accepted: December 13, 2022; Published online: January 16, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by tremors, bradykinesia, and rigidity. PD is caused by loss of dopaminergic (DA) neurons in the midbrain substantia nigra (SN) and therefore, replenishment of DA neurons via stem cell-based therapy is a potential treatment option. Astrocytes are the most abundant non-neuronal cells in the central nervous system and are promising candidates for reprogramming into neuronal cells because they share a common origin with neurons. The ability of neural progenitor cells (NPCs) to proliferate and differentiate may overcome the limitations of the reduced viability and function of transplanted cells after cell replacement therapy. Achaete-scute complex homolog-like 1 (Ascl1) is a wellknown neuronal-specific factor that induces various cell types such as human and mouse astrocytes and fibroblasts to differentiate into neurons. Nurr1 is involved in the differentiation and maintenance of DA neurons, and decreased Nurr1 expression is known to be a major risk factor for PD. Previous studies have shown that direct conversion of astrocytes into DA neurons and NPCs can be induced by overexpression of Ascl1 and Nurr1 and additional transcription factors genes such as superoxide dismutase 1 and SRY-box 2. Here, we demonstrate that astrocytes isolated from the ventral midbrain, the origin of SN DA neurons, can be effectively converted into DA neurons and NPCs with enhanced viability. In addition, when these NPCs are inducted to differentiate, they exhibit key characteristics of DA neurons. Thus, direct conversion of midbrain astrocytes is a possible cell therapy strategy to treat neurodegenerative diseases.
Keywords: Dopaminergic neurons, Transdifferentiation, Ventral midbrain, Astrocytes

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