Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease

J Clin Invest. 2011 Jun;121(6):2326-35. doi: 10.1172/JCI45794. Epub 2011 May 16.

Abstract

Parkinson disease (PD) involves the selective loss of midbrain dopamine (mDA) neurons and is a possible target disease for stem cell-based therapy. Human induced pluripotent stem cells (hiPSCs) are a potentially unlimited source of patient-specific cells for transplantation. However, it is critical to evaluate the safety of hiPSCs generated by different reprogramming methods. Here, we compared multiple hiPSC lines derived by virus- and protein-based reprogramming to human ES cells (hESCs). Neuronal precursor cells (NPCs) and dopamine (DA) neurons delivered from lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes, but those cells derived from retrovirus- and protein-based hiPSCs did not. Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging, which was preceded by abrupt induction of p53. In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence. DA neurons derived from protein-based hiPSCs exhibited gene expression, physiological, and electrophysiological properties similar to those of mDA neurons. Transplantation of these cells into rats with striatal lesions, a model of PD, significantly rescued motor deficits. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of PD.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Arginine
  • Cell Differentiation
  • Cell Line / transplantation
  • Cell Lineage
  • Cellular Reprogramming*
  • Cellular Senescence
  • Dopamine / metabolism*
  • Gene Expression Regulation, Developmental
  • Genes, p53
  • Genetic Vectors / pharmacology
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Induced Pluripotent Stem Cells / transplantation
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / physiology*
  • Lentivirus / physiology
  • Neurons / cytology*
  • Neurons / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / physiology*
  • Parkinsonian Disorders / surgery*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / physiology*
  • Rats
  • Retroviridae / physiology
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / physiology*
  • Tumor Suppressor Protein p53 / biosynthesis

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Proto-Oncogene Proteins c-myc
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Arginine
  • Dopamine