Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

Yongwoo Yoon,Zhong Pei,Hyun Jung Park,Endan Li,Chang Pyo Hong,Jihwan Song,Nayeon Lee,Iksoo Jeon,Hyun Sook Kim

doi:10.3389/fnins.2020.558204

Abstract

Huntington’s disease (HD) is a devastating, autosomal-dominant inheritance disorder with the progressive loss of medium spiny neurons (MSNs) and corticostriatal connections in the brain. Cell replacement therapy has been proposed as a potential therapeutic strategy to treat HD. Among various types of stem cells, human-induced pluripotent stem cells (iPSCs) have received special attention to develop disease modeling and cell therapy for HD. In the present study, the therapeutic effects of neural precursor cells (NPCs) derived from a human iPSC line (1231A3-NPCs) were investigated in the quinolinic acid (QA)-lesioned rat model of HD. 1231A3-NPCs were transplanted into the ipsilateral striatum 1 week after QA lesioning, and the transplanted animals showed significant behavioral improvements for up to 12 weeks based on the staircase, rotarod, stepping, apomorphine-induced rotation, and cylinder tests. Transplanted 1231A3-NPCs also partially replaced the lost neurons, enhanced endogenous neurogenesis, reduced inflammatory responses, and reconstituted the damaged neuronal connections. Taken together, these results strongly indicate that NPCs derived from iPSCs can potentially be useful to treat HD in the future.

Highlights

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the abnormal expansion of cytosine-adenine-guanine (CAG) repeats in exon 1 of the huntingtin gene, which encodes a 350-kDa protein termed Huntingtin (MacDonald, 1993)
The differences in the number of retrieved pellets were greater in the 1231A3-neural precursor cells (NPCs) TP group compared with the fibroblast TP and sham groups from 8 weeks post-TP (p < 0.0001 for the 1231A3NPC TP group compared with the fibroblast TP group, p < 0.04 for the 1231A3-NPC TP group compared with the sham group; Figure 1A)
Group difference of falling latency increased progressively over time (p < 0.03 for the 1231A3-NPC TP group compared with the fibroblast TP group at 6 weeks post-TP, p < 0.01 for the 1231A3-NPC TP group compared with the sham group at 8 weeks post-TP, and p < 0.001 for the 1231A3-NPC TP group compared with the sham group at 12 weeks post-TP; Figure 1B)

Summary

Introduction

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the abnormal expansion of cytosine-adenine-guanine (CAG) repeats in exon 1 of the huntingtin gene, which encodes a 350-kDa protein termed Huntingtin (MacDonald, 1993). The disease onset typically occurs in middle-aged people in correlation with the length of the CAG expansion (Duyao et al, 1993; Aziz et al, 2018), and the mutation largely causes degeneration of striatal medium spiny neurons (MSNs), resulting in the atrophy of caudate nucleus and putamen, as well as disturbed functions of the basal ganglia in the patient’s brain. Standardization and ethical issues associated with the use of aborted human fetal tissues caused serious limitations (Bjorklund, 1993; Vazey et al, 2006). To overcome these limitations, induced pluripotent stem cells (iPSCs) have emerged as useful candidate cells to treat HD. Because HD is a genetic disease, correction of the mutated gene will be essential for autologous cell therapy (An et al, 2012; Csobonyeiova et al, 2020)

Methods

Results

Conclusion