Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

Dustin R. Wakeman; Benjamin M. Hiller; David J. Marmion; Christopher W. McMahon; Grant T. Corbett; Kile P. Mangan; Junyi Ma; Lauren E. Little; Zhong Xie; Tamara Perez-Rosello; Jaime N. Guzman; D. James Surmeier; Jeffrey H. Kordower

doi:10.1016/j.stemcr.2017.04.033

Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

Dustin R. Wakeman^*, Benjamin M. Hiller, David J. Marmion, Christopher W. McMahon, Grant T. Corbett, Kile P. Mangan, Junyi Ma, Lauren E. Little, Zhong Xie, Tamara Perez-Rosello, Jaime N. Guzman, D. James Surmeier, Jeffrey H. Kordower

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

Original language	English (US)
Pages (from-to)	149-161
Number of pages	13
Journal	Stem cell reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1016/j.stemcr.2017.04.033
State	Published - Jul 11 2017

Keywords

6-OHDA
MPTP
Parkinson's disease
cryopreservation
iPSC
midbrain dopamine neuron
non-human primate

ASJC Scopus subject areas

Genetics
Biochemistry
Cell Biology
Developmental Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.stemcr.2017.04.033

Cite this

Wakeman, D. R., Hiller, B. M., Marmion, D. J., McMahon, C. W., Corbett, G. T., Mangan, K. P., Ma, J., Little, L. E., Xie, Z., Perez-Rosello, T., Guzman, J. N., Surmeier, D. J., & Kordower, J. H. (2017). Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo. Stem cell reports, 9(1), 149-161. https://doi.org/10.1016/j.stemcr.2017.04.033

@article{f057979e04074c6abfbc65211d738c4c,

title = "Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo",

abstract = "A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.",

keywords = "6-OHDA, MPTP, Parkinson's disease, cryopreservation, iPSC, midbrain dopamine neuron, non-human primate",

author = "Wakeman, {Dustin R.} and Hiller, {Benjamin M.} and Marmion, {David J.} and McMahon, {Christopher W.} and Corbett, {Grant T.} and Mangan, {Kile P.} and Junyi Ma and Little, {Lauren E.} and Zhong Xie and Tamara Perez-Rosello and Guzman, {Jaime N.} and Surmeier, {D. James} and Kordower, {Jeffrey H.}",

note = "Funding Information: We thank Clive N. Svendsen for providing the human fetal cortical neural stem cells, Rachel Harker and Scott Muller for exceptional primate husbandry, Cedric Bardy and the Salk Institute for providing the BrainPhys medium used in MEA analysis, Carrie Chavez and Lucas Chase for technical expertise, and Kim Staats for editorial suggestions to the manuscript. This work was supported in part by grants to D.R.W. from Rush University Medical Center: Department of Neurological Sciences and Translational Sciences Consortium, as well as funding from Cellular Dynamics International, Inc. J.H.K. was supported by a center grant from the Parkinson's disease Foundation. This work also was supported by grants from the JPB Foundation and NIH (NS NS047085) to D.J.S. C.W.M., K.P.M., L.E.L., and J.M. are employees at Cellular Dynamics International, Inc. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = jul,

day = "11",

doi = "10.1016/j.stemcr.2017.04.033",

language = "English (US)",

volume = "9",

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Wakeman, DR, Hiller, BM, Marmion, DJ, McMahon, CW, Corbett, GT, Mangan, KP, Ma, J, Little, LE, Xie, Z, Perez-Rosello, T, Guzman, JN , Surmeier, DJ & Kordower, JH 2017, 'Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo', Stem cell reports, vol. 9, no. 1, pp. 149-161. https://doi.org/10.1016/j.stemcr.2017.04.033

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T1 - Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

AU - Wakeman, Dustin R.

AU - Hiller, Benjamin M.

AU - Marmion, David J.

AU - McMahon, Christopher W.

AU - Corbett, Grant T.

AU - Mangan, Kile P.

AU - Ma, Junyi

AU - Little, Lauren E.

AU - Xie, Zhong

AU - Perez-Rosello, Tamara

AU - Guzman, Jaime N.

AU - Surmeier, D. James

AU - Kordower, Jeffrey H.

N1 - Funding Information: We thank Clive N. Svendsen for providing the human fetal cortical neural stem cells, Rachel Harker and Scott Muller for exceptional primate husbandry, Cedric Bardy and the Salk Institute for providing the BrainPhys medium used in MEA analysis, Carrie Chavez and Lucas Chase for technical expertise, and Kim Staats for editorial suggestions to the manuscript. This work was supported in part by grants to D.R.W. from Rush University Medical Center: Department of Neurological Sciences and Translational Sciences Consortium, as well as funding from Cellular Dynamics International, Inc. J.H.K. was supported by a center grant from the Parkinson's disease Foundation. This work also was supported by grants from the JPB Foundation and NIH (NS NS047085) to D.J.S. C.W.M., K.P.M., L.E.L., and J.M. are employees at Cellular Dynamics International, Inc. Publisher Copyright: © 2017 The Author(s)

PY - 2017/7/11

Y1 - 2017/7/11

N2 - A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

AB - A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

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