Mitomycin-C treatment during differentiation of induced pluripotent stem cell-derived dopamine neurons reduces proliferation without compromising survival or function in vivo

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)278-290
Number of pages13
JournalStem cells translational medicine
Volume10
Issue number2
DOIs
StatePublished - Feb 2021
Externally publishedYes

Keywords

  • cell transplantation
  • immune-deficient models
  • induced pluripotent stem cells
  • Parkinson's disease

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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