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Functional Recovery from Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts is Dependent on Neurite Outgrowth

View ORCID ProfileRachel Hills, View ORCID ProfileJim A. Mossman, Andres M. Bratt-Leal, Ha Tran, Roy M. Williams, David G. Stouffer, Irina V. Sokolova, View ORCID ProfilePietro P. Sanna, View ORCID ProfileJeanne F. Loring, View ORCID ProfileMariah J. Lelos
doi: https://doi.org/10.1101/2022.04.19.488213
Rachel Hills
1Brain Repair Group, School of Biosciences, Museum Avenue, Cardiff University, Cardiff, CF10 3AX, U.K.
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  • ORCID record for Rachel Hills
Jim A. Mossman
2Aspen Neuroscience, Inc. 10835 Road to the Cure, Ste. 100, San Diego, CA, 92121 USA
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Andres M. Bratt-Leal
3Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
4Summit For Stem Cell Foundation, San Diego, California, USA
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Ha Tran
3Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
4Summit For Stem Cell Foundation, San Diego, California, USA
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Roy M. Williams
3Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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David G. Stouffer
3Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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Irina V. Sokolova
5Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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Pietro P. Sanna
5Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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Jeanne F. Loring
3Department of Molecular Medicine, Center for Regenerative Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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  • For correspondence: lelosmj@cardiff.ac.uk
Mariah J. Lelos
1Brain Repair Group, School of Biosciences, Museum Avenue, Cardiff University, Cardiff, CF10 3AX, U.K.
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  • For correspondence: lelosmj@cardiff.ac.uk
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Summary

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 Statement

There 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.

Footnotes

  • ↵* Joint senior authors

  • https://www.ncbi.nlm.nih.gov/geo/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 19, 2022.
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Functional Recovery from Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts is Dependent on Neurite Outgrowth
Rachel Hills, Jim A. Mossman, Andres M. Bratt-Leal, Ha Tran, Roy M. Williams, David G. Stouffer, Irina V. Sokolova, Pietro P. Sanna, Jeanne F. Loring, Mariah J. Lelos
bioRxiv 2022.04.19.488213; doi: https://doi.org/10.1101/2022.04.19.488213
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Functional Recovery from Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts is Dependent on Neurite Outgrowth
Rachel Hills, Jim A. Mossman, Andres M. Bratt-Leal, Ha Tran, Roy M. Williams, David G. Stouffer, Irina V. Sokolova, Pietro P. Sanna, Jeanne F. Loring, Mariah J. Lelos
bioRxiv 2022.04.19.488213; doi: https://doi.org/10.1101/2022.04.19.488213

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