Reduced dopaminergic neuron degeneration and global transcriptional changes in Parkinson's disease mouse brains engrafted with human neural stems during the early disease stage

Abstract

Introduction: Current stem cell therapies for Parkinson's disease (PD) focus on a neurorestorative approach that aims to repair the CNS during the symptomatic phase. However, the pleiotropic and supportive effects of human neural stem cells (hNSCs) may make them effective for PD treatment during the disease's earlier stages. In the current study, we investigated the therapeutic effects of transplanting hNSCs during the early stages of PD development when most dopaminergic neurons are still present and before symptoms appear. Previous studies on hNSCs in Parkinson's disease focus on the substantia nigra and its immediate surroundings, but other brain structures are affected in PD as well. Here, we investigated the therapeutic effects of hNSCs on the entire PD-afflicted brain transcriptome using RNA sequencing (RNA-seq).

Methods: PD was induced with a single intranasal infusion of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and hNSCs were transplanted unilaterally into the striatum one week later. The timepoint for hNSC transplantation coincided with upregulation of endogenous proinflammatory cytokines in the CNS, which play a role in stem cell migration. At 3 weeks post-transplantation (4 weeks post-MPTP), we assessed motor symptoms through behavioral tests, quantified dopaminergic neurons in the substantia nigra, and performed global transcriptional profiling to understand the mechanism underlying the effect of hNSCs on dopaminergic neuron degeneration.

Results: We found that early hNSC engraftment mitigated motor symptoms induced by MPTP, and also reduced MPTP-induced loss of dopaminergic neurons. In this study, we uniquely presented the first comprehensive analysis of the effect of hNSC transplantation on the transcriptional profiling of PD mouse brains showing decreased expression of 249 and increased expression of 200 genes. These include genes implicated in mitochondrial bioenergetics, proteostasis, and other signaling pathways associated with improved PD outcome following hNSC transplantation.

Conclusion: These findings indicate that NSC transplantation during the asymptomatic phase of PD may limit or halt the progression of this neurodegenerative disorder. Transcriptional profiling of hNSC-engrafted PD mouse brains provides mechanistic insight that could lead to novel approaches to ameliorating degeneration of dopaminergic neurons and improving behavioral dysfunction in PD.

Keywords: Dopaminergic neuron; Ingenuity pathway analysis; MPTP; Neural stem cells; Parkinson's disease; RNA sequencing; Transcriptome; Transplantation; Tyrosine hydroxylase.