RT Journal Article
SR Electronic
T1 Functional Recovery from Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts is Dependent on Neurite Outgrowth
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.19.488213
DO 10.1101/2022.04.19.488213
A1 Rachel Hills
A1 Jim A. Mossman
A1 Andres M. Bratt-Leal
A1 Ha Tran
A1 Roy M. Williams
A1 David G. Stouffer
A1 Irina V. Sokolova
A1 Pietro P. Sanna
A1 Jeanne F. Loring
A1 Mariah J. Lelos
YR 2022
UL http://biorxiv.org/content/early/2022/04/19/2022.04.19.488213.abstract
AB Transplantation of human pluripotent stem cell-derived dopaminergic (DA) neurons is an emerging therapeutic strategy for Parkinson’s disease (PD). In this study, we demonstrate, for the first time, that that functional recovery after DA neuron transplant is critically dependent on graft-host integration, and not dependent on graft size or DA neuron content. Specifically, in anticipation of an autologous DA neuron transplant strategy, we studied two human induced pluripotent stem cell lines derived from people with idiopathic PD. We confirmed the cells’ ability to differentiate into mature DA neurons in vitro by assessing electrophysiology and depolarization-induced neurotransmitter release. To evaluate efficacy, we transplanted DA neuron precursors into a hemiparkinsonian rat model. We differentiated the cell lines for either 18 (d18) or 25 days (d25) to investigate the effect of cell maturity on efficacy. We found comparable graft survival in d18 and d25 groups from both cell lines, but behavioral analysis revealed that only d18 preparations, from both cell lines, resulted in recovery of motor impairments. Immunohistochemical analysis did not reveal any DA neuron-associated markers that correlated with efficacy. However, we found striking and consistent differences in graft neurite outgrowth between the two culture timepoints. The functional grafts from d18 cells had more outgrowth than non-functional d25 grafts. A time course of gene expression during differentiation of the cell lines revealed differences in genes associated with DA neuron development and neurite plasticity. These results are the first to demonstrate that graft-host integration, and not DA neuron content, is key to graft-induced functional recovery. The gene expression profiling may offer insight into the optimal developmental stage for graft efficacy.Competing Interest StatementThere are no conflicts of interest. All of the data were generated at Scripps Research Institute or Cardiff University with the financial support indicated. JFL and ABL are stockholders and founders of Aspen Neuroscience, Inc. (Aspen). HT, RMW, and JAM are stockholders in Aspen.