Differentiation and characterization of dopaminergic neurons from baboon induced pluripotent stem cells

Douglas A. Grow, Denard V. Simmons, Jorge A. Gomez, Matthew J. Wanat, John R. McCarrey, Carlos A. Paladini, Christopher S. Navara

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The progressive death of dopamine producing neurons in the substantia nigra pars compacta is the principal cause of symptoms of Parkinson’s disease (PD). Stem cells have potential therapeutic use in replacing these cells and restoring function. To facilitate development of this approach, we sought to establish a preclinical model based on a large nonhuman primate for testing the efficacy and safety of stem cell-based transplantation. To this end, we differentiated baboon fibroblast-derived induced pluripotent stem cells (biPSCs) into dopaminergic neurons with the application of specific morphogens and growth factors. We confirmed that biPSC-derived dopaminergic neurons resemble those found in the human midbrain based on cell type-specific expression of dopamine markers TH and GIRK2. Using the reverse transcriptase quantitative polymerase chain reaction, we also showed that biPSC-derived dopaminergic neurons express PAX6, FOXA2, LMX1A, NURR1, and TH genes characteristic of this cell type in vivo. We used perforated patch-clamp electrophysiology to demonstrate that biPSC-derived dopaminergic neurons fired spontaneous rhythmic action potentials and highfrequency action potentials with spike frequency adaption upon injection of depolarizing current. Finally, we showed that biPSC-derived neurons released catecholamines in response to electrical stimulation. These results demonstrate the utility of the baboon model for testing and optimizing the efficacy and safety of stem cell-based therapeutic approaches for the treatment of PD.

Original languageEnglish (US)
Pages (from-to)1133-1144
Number of pages12
JournalStem Cells Translational Medicine
Volume5
Issue number9
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Baboon
  • Dopaminergic neurons
  • Induced pluripotent stem cells
  • Neural differentiation
  • Parkinson’s disease

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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