Efficient generation of dopamine neurons from mouse ventral midbrain astrocytes

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder accompanied by tremors, bradykinesia, and rigidity. As PD is caused by loss of dopaminergic (DA) neurons in the midbrain substantia nigra (SN), thus, replenishment of DA neurons via stem cell-based therapy. 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. In addition, there is an aberrant increase in the number of astrocytes in PD owing to the destruction of neurons in neurodegenerative diseases. Therefore, considering the in vivo environment of the disease model, astrocytes are suitable for direct conversion into neurons. The ability of neural progenitor cells (NPCs) to proliferate and differentiate is a way to 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 well-known 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. 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 (SOD1) and SOX2. Here, we demonstrated that astrocytes isolated from the ventral midbrain, which is the origin of SN DA neurons, could be effectively converted into DA neurons and NPCs, and the viability of the reprogrammed cells could be enhanced. In addition, we observed that when the established induced-NPCs became differentiated, they exhibited key characteristics of DA neurons. Thus, direct conversion of midbrain astrocytes appears to be a possible cell therapy strategy to treat neurodegenerative diseases.