Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo
Abstract Nongenetic methodologies to reduce undesirable proliferation would be valuable when generating dopamine neurons from stem cells for transplantation in Parkinson's disease (PD). To this end, we modified an established method for controlled differentiation of human induced pluripotent st...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Oxford University Press
2021-02-01
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| Series: | Stem Cells Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/sctm.20-0014 |
| _version_ | 1819003585095008256 |
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| author | Benjamin M. Hiller David J. Marmion Rachel M. Gross Cayla A. Thompson Carrie A. Chavez Patrik Brundin Dustin R. Wakeman Christopher W. McMahon Jeffrey H. Kordower |
| author_facet | Benjamin M. Hiller David J. Marmion Rachel M. Gross Cayla A. Thompson Carrie A. Chavez Patrik Brundin Dustin R. Wakeman Christopher W. McMahon Jeffrey H. Kordower |
| author_sort | Benjamin M. Hiller |
| collection | DOAJ |
| description | Abstract Nongenetic methodologies to reduce undesirable proliferation would be valuable when generating dopamine neurons from stem cells for transplantation in Parkinson's disease (PD). To this end, we modified an established method for controlled differentiation of human induced pluripotent stem cells (iPSCs) into midbrain dopamine neurons using two distinct methods: omission of FGF8 or the in‐process use of the DNA cross‐linker mitomycin‐C (MMC). We transplanted the cells to athymic rats with unilateral 6‐hydroxydopamine lesions and monitored long‐term survival and function of the grafts. Transplants of cells manufactured using MMC had low proliferation while still permitting robust survival and function comparable to that seen with transplanted dopamine neurons derived using genetic drug selection. Conversely, cells manufactured without FGF8 survived transplantation but exhibited poor in vivo function. Our results suggest that MMC can be used to reduce the number of proliferative cells in stem cell‐derived postmitotic neuron preparations for use in PD cell therapy. |
| first_indexed | 2024-12-20T23:23:20Z |
| format | Article |
| id | doaj.art-f01fe3c0dbb64c11a6b43d6f7c6c3c41 |
| institution | Directory Open Access Journal |
| issn | 2157-6564 2157-6580 |
| language | English |
| last_indexed | 2024-12-20T23:23:20Z |
| publishDate | 2021-02-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Stem Cells Translational Medicine |
| spelling | doaj.art-f01fe3c0dbb64c11a6b43d6f7c6c3c412022-12-21T19:23:27ZengOxford University PressStem Cells Translational Medicine2157-65642157-65802021-02-0110227829010.1002/sctm.20-0014Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivoBenjamin M. Hiller0David J. Marmion1Rachel M. Gross2Cayla A. Thompson3Carrie A. Chavez4Patrik Brundin5Dustin R. Wakeman6Christopher W. McMahon7Jeffrey H. Kordower8Department of Neurological Sciences Rush University Chicago Illinois USADepartment of Neurological Sciences Rush University Chicago Illinois USACollege of Arts and Science, Vanderbilt University Nashville Tennessee USAFujifilm Cellular Dynamics, Inc. Madison Wisconsin USAFujifilm Cellular Dynamics, Inc. Madison Wisconsin USACenter for Neurodegenerative Science, Van Andel Institute Grand Rapids Michigan USAVirscio, Inc. New Haven Connecticut USAFujifilm Cellular Dynamics, Inc. Madison Wisconsin USADepartment of Neurological Sciences Rush University Chicago Illinois USAAbstract Nongenetic methodologies to reduce undesirable proliferation would be valuable when generating dopamine neurons from stem cells for transplantation in Parkinson's disease (PD). To this end, we modified an established method for controlled differentiation of human induced pluripotent stem cells (iPSCs) into midbrain dopamine neurons using two distinct methods: omission of FGF8 or the in‐process use of the DNA cross‐linker mitomycin‐C (MMC). We transplanted the cells to athymic rats with unilateral 6‐hydroxydopamine lesions and monitored long‐term survival and function of the grafts. Transplants of cells manufactured using MMC had low proliferation while still permitting robust survival and function comparable to that seen with transplanted dopamine neurons derived using genetic drug selection. Conversely, cells manufactured without FGF8 survived transplantation but exhibited poor in vivo function. Our results suggest that MMC can be used to reduce the number of proliferative cells in stem cell‐derived postmitotic neuron preparations for use in PD cell therapy.https://doi.org/10.1002/sctm.20-0014cell transplantationimmune‐deficient modelsinduced pluripotent stem cellsParkinson's disease |
| spellingShingle | Benjamin M. Hiller David J. Marmion Rachel M. Gross Cayla A. Thompson Carrie A. Chavez Patrik Brundin Dustin R. Wakeman Christopher W. McMahon Jeffrey H. Kordower Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo Stem Cells Translational Medicine cell transplantation immune‐deficient models induced pluripotent stem cells Parkinson's disease |
| title | Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| title_full | Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| title_fullStr | Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| title_full_unstemmed | Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| title_short | Mitomycin‐C treatment during differentiation of induced pluripotent stem cell‐derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| title_sort | mitomycin c treatment during differentiation of induced pluripotent stem cell derived dopamine neurons reduces proliferation without compromising survival or function in vivo |
| topic | cell transplantation immune‐deficient models induced pluripotent stem cells Parkinson's disease |
| url | https://doi.org/10.1002/sctm.20-0014 |
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