Somatic cell reprogramming for Parkinson's disease treatment

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration of dopamine neurons in the substantia nigra pars compacta. The patient exhibits a series of motor symptoms, such as static tremors, which impair their capacity to take care for themselves in daily life. In the late stage, the patient is unable to walk independently and is bedridden for an extended period of time, reducing their quality of life significantly. So far, treatment methods for PD mainly include drug therapy and deep brain stimulation. Pharmacotherapy is aimed at increasing dopamine (DA) levels; however, the treatment effect is more pronounced in the short term, and there is no benefit in improvement in the overall progression of the disease. In recent years, novel therapeutic strategies have been developed, such as cell reprogramming, trying to generate more DA in PD treatment. This review mainly discusses the advantages, methodology, cell origin, transformation efficiency, and practical application shortcomings of cell reprogramming therapy in PD strategy.

Keywords: Parkinson's disease; cell reprogramming; lineage reprogramming.

Figure 1

The two major reprogramming strategies. (A) Somatic cells such as astrocytes, microglia, and fibroblasts obtained from monkeys and mice, a type of iPSC obtained by indirect reprogramming and then induced differentiation into dopaminergic neurons, were then transplanted into PD host brains. The other cells are directly reprogrammed into dopaminergic neurons and transplanted them into PD host brains. (B) In the striatum site of the brain of the PD host that enriches the astrocyte population, the orthotopic astrocytes are directly reprogrammed into dopaminergic neurons by viruses, protein molecules, nanomaterials, small molecules, and drug induction. iDANs, induced DA neurons; iPSC, induced pluripotent stem cells; PD, Parkinson's disease. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Methods for increasing the proportion of A9 subsets and for purification of the induced cells. (A) Based on optimal physical, chemical, and developmental cues, the researchers developed an efficient and reliable in vitro differentiation method, termed “spotting” method. (B) Lentiviral vectors were used to drive LMX1A overexpression, resulting in the differentiation of LMX1A‐engineered hESCs to obtain dopaminergic neurons with a high proportion of A9. (C) After DAergic neural progenitor cells were transplanted into the brain of PD rats, the proportion of neuron differentiation in the A9 subset was increased by levodopa combined induction. Methods for purification of the induced cells. Small molecules such as γ secretase inhibitors (D), quercetin (E) are used to inhibit Notch signaling in dopaminergic neural progenitor cell, or specific receptors are designed as cell surface markers to selectively eliminate cells (F), or adjuvant radiation therapy after radiation transplantation (G), and cells are purified by RNA switching (H). DAP, dopaminergic neural progenitor cell; hESC, human embryonic stem cell; l‐DOPA, dihydroxyphenylalanine; Girk2+, G‐protein‐activated inward rectifier potassium channel 2; GSI, γ‐secretase inhibitors; iNSC, induced neural stem cell; NPC, neuropithelial cell; NICD, Notch intracellular domain; TM, transmembrane domain. [Color figure can be viewed at wileyonlinelibrary.com]