Neurite outgrowth and gene expression profile correlate with efficacity of human induced pluripotent stem cell-derived dopamine neuron grafts

Hills, Rachel, Mossman, Jim A., Bratt-Leal, Andres M., Tran, Ha, Williams, Roy M., Stouffer, David G., Sokolova, Irina V., Sanna, Pietro P., Loring, Jeanne F. and Lelos, Mariah J. ORCID: https://orcid.org/0000-0001-7102-055X 2023. Neurite outgrowth and gene expression profile correlate with efficacity of human induced pluripotent stem cell-derived dopamine neuron grafts. Stem Cells and Development 32 (13-14) , pp. 387-397. 10.1089/scd.2023.0043

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Publisher:	Mary Ann Liebert
ISSN:	1547-3287
Funders:	Parkinson's UK
Date of First Compliant Deposit:	26 June 2023
Date of Acceptance:	8 May 2023
Last Modified:	07 Nov 2023 01:34
URI:	https://orca.cardiff.ac.uk/id/eprint/160549

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