Functional characterization of Friedreich ataxia iPS-derived neuronal progenitors and their integration in the adult brain

PLoS One. 2014 Jul 7;9(7):e101718. doi: 10.1371/journal.pone.0101718. eCollection 2014.

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that is caused by an insufficiency of the mitochondrial protein, frataxin. Our previous studies described the generation of FRDA induced pluripotent stem cell lines (FA3 and FA4 iPS) that retained genetic characteristics of this disease. Here we extend these studies, showing that neural derivatives of FA iPS cells are able to differentiate into functional neurons, which don't show altered susceptibility to cell death, and have normal mitochondrial function. Furthermore, FA iPS-derived neural progenitors are able to differentiate into functional neurons and integrate in the nervous system when transplanted into the cerebellar regions of host adult rodent brain. These are the first studies to describe both in vitro and in vivo characterization of FA iPS-derived neurons and demonstrate their capacity to survive long term. These findings are highly significant for developing FRDA therapies using patient-derived stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Death
  • Cell Differentiation
  • Cell Line
  • Cell Survival
  • Cerebellum / cytology*
  • Female
  • Frataxin
  • Friedreich Ataxia / pathology*
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Iron-Binding Proteins / metabolism
  • Mitochondria / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Rats

Substances

  • Iron-Binding Proteins

Grants and funding

These studies were supported by the Friedreich's Ataxia Research Association USA (www.curefa.org) and Australasia (www.fara.org.au/) (MD), the Australian Mitochondrial Disease Foundation (www.amdf.org.au/) (MJB), an Australian Postgraduate Award (http://services.unimelb.edu.au/scholarships/research/local/available/apa) (MJB), a Principal Research Fellowship (DRT), Career Development Awards (AEF, LHT) and a Medical Research Council Peter Doherty Fellowship (BAN) all from the Australian National Health and Medical Research Council (www.nhmrc.gov.au/), a Victorian Government's Operational Infrastructure Support Program (http://www.business.vic.gov.au/industries/science-technology-and-innovation/programs/medical-research-operational-infrastructure-program), a senior medical research fellowship (CLP) provided by the Viertel charitable foundation (www.anz.com.au/personal/private-bank…/scholarships-fellowships/), and a Brain Foundation Award (brainfoundation.org.au). The authors would also like to thank Brian Mendenhall from the USC High Performance Computing Cluster for installing and testing high content analysis software. The authors declare no conflict of interest relating to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.