Neurite Outgrowth and Gene Expression Profile Correlate with Efficacy of Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts.
Neurite Outgrowth and Gene Expression Profile Correlate with Efficacy of Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Cardiff, GB · Author affiliation
Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.Location evidence
US · Author affiliation · country only
Independent Bioinformatics Consultant, Del Mar, California, USA.Location evidence
La Jolla, US · Author affiliation
Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, La Jolla, California, USA.Location evidence
Summit, US · Author affiliation
Summit for Stem Cell Foundation, San Diego, California, USA.Location evidence
San Diego, US · Author affiliation
Summit for Stem Cell Foundation, San Diego, California, USA.Location evidence
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Original abstract
Transplantation of human induced pluripotent stem cell-derived dopaminergic (iPSC-DA) neurons is a promising therapeutic strategy for Parkinson's disease (PD). To assess optimal cell characteristics and reproducibility, we evaluated the efficacy of iPSC-DA neuron precursors from two individuals with sporadic PD by transplantation into a hemiparkinsonian rat model after differentiation for either 18 (d18) or 25 days (d25). We found similar graft size and dopamine (DA) neuron content in both groups, but only the d18 cells resulted in recovery of motor impairments. In contrast, we report that d25 grafts survived equally as well and produced grafts rich in tyrosine hydroxylase-positive neurons, but were incapable of alleviating any motor deficits. We identified the mechanism of action as the extent of neurite outgrowth into the host brain, with d18 grafts supporting significantly more neurite outgrowth than nonfunctional d25 grafts. RNAseq analysis of the cell preparation suggests that graft efficacy may be enhanced by repression of differentiation-associated genes by REST, defining the optimal predifferentiation state for transplantation. This study demonstrates for the first time that DA neuron grafts can survive well in vivo while completely lacking the capacity to induce recovery from motor dysfunction. In contrast to other recent studies, we demonstrate that neurite outgrowth is the key factor determining graft efficacy and our gene expression profiling revealed characteristics of the cells that may predict their efficacy. These data have implication for the generation of DA neuron grafts for clinical application.