Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease
Abstract In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-04-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-022-00221-y |
| _version_ | 1818127830797516800 |
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| author | Benjamin M. Hiller David J. Marmion Cayla A. Thompson Nathaniel A. Elliott Howard Federoff Patrik Brundin Virginia B. Mattis Christopher W. McMahon Jeffrey H. Kordower |
| author_facet | Benjamin M. Hiller David J. Marmion Cayla A. Thompson Nathaniel A. Elliott Howard Federoff Patrik Brundin Virginia B. Mattis Christopher W. McMahon Jeffrey H. Kordower |
| author_sort | Benjamin M. Hiller |
| collection | DOAJ |
| description | Abstract In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to the ventral midbrain demonstrated that D17 cells had a greater capacity than D24 cells to innervate over long distance to forebrain structures, including the striatum. When D17 cells were assessed across a wide dose range (7,500-450,000 injected cells per striatum), there was a clear dose response with regards to numbers of surviving neurons, innervation, and functional recovery. Importantly, although these grafts were derived from iPSCs, we did not observe teratoma formation or significant outgrowth of other cells in any animal. These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development with the aim of transplantation trials in patients with Parkinson’s disease. |
| first_indexed | 2024-12-11T07:23:36Z |
| format | Article |
| id | doaj.art-935613851567435890b73366f2592369 |
| institution | Directory Open Access Journal |
| issn | 2057-3995 |
| language | English |
| last_indexed | 2024-12-11T07:23:36Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj.art-935613851567435890b73366f25923692022-12-22T01:16:02ZengNature Portfolionpj Regenerative Medicine2057-39952022-04-017111510.1038/s41536-022-00221-yOptimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s diseaseBenjamin M. Hiller0David J. Marmion1Cayla A. Thompson2Nathaniel A. Elliott3Howard Federoff4Patrik Brundin5Virginia B. Mattis6Christopher W. McMahon7Jeffrey H. Kordower8Department of Neurological Sciences, Rush University Medical CenterDepartment of Neurological Sciences, Rush University Medical CenterFUJIFILM Cellular Dynamics Inc.FUJIFILM Cellular Dynamics Inc.Brooklyn ImmunoTherapeuticsParkinson’s Disease Center, Department for Neurodegenerative Science, Van Andel InstituteFUJIFILM Cellular Dynamics Inc.FUJIFILM Cellular Dynamics Inc.Department of Neurological Sciences, Rush University Medical CenterAbstract In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to the ventral midbrain demonstrated that D17 cells had a greater capacity than D24 cells to innervate over long distance to forebrain structures, including the striatum. When D17 cells were assessed across a wide dose range (7,500-450,000 injected cells per striatum), there was a clear dose response with regards to numbers of surviving neurons, innervation, and functional recovery. Importantly, although these grafts were derived from iPSCs, we did not observe teratoma formation or significant outgrowth of other cells in any animal. These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development with the aim of transplantation trials in patients with Parkinson’s disease.https://doi.org/10.1038/s41536-022-00221-y |
| spellingShingle | Benjamin M. Hiller David J. Marmion Cayla A. Thompson Nathaniel A. Elliott Howard Federoff Patrik Brundin Virginia B. Mattis Christopher W. McMahon Jeffrey H. Kordower Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease npj Regenerative Medicine |
| title | Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease |
| title_full | Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease |
| title_fullStr | Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease |
| title_full_unstemmed | Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease |
| title_short | Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease |
| title_sort | optimizing maturity and dose of ipsc derived dopamine progenitor cell therapy for parkinson s disease |
| url | https://doi.org/10.1038/s41536-022-00221-y |
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