Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells

Cell Res. 2012 Feb;22(2):321-32. doi: 10.1038/cr.2011.181. Epub 2011 Nov 22.

Abstract

Transplantation of exogenous dopaminergic neuron (DA neurons) is a promising approach for treating Parkinson's disease (PD). However, a major stumbling block has been the lack of a reliable source of donor DA neurons. Here we show that a combination of five transcriptional factors Mash1, Ngn2, Sox2, Nurr1, and Pitx3 can directly and effectively reprogram human fibroblasts into DA neuron-like cells. The reprogrammed cells stained positive for various markers for DA neurons. They also showed characteristic DA uptake and production properties. Moreover, they exhibited DA neuron-specific electrophysiological profiles. Finally, they provided symptomatic relief in a rat PD model. Therefore, our directly reprogrammed DA neuron-like cells are a promising source of cell-replacement therapy for PD.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation
  • Cellular Reprogramming*
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / cytology*
  • Dopaminergic Neurons / transplantation
  • Fibroblasts / cytology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Parkinson Disease / therapy
  • Rats
  • Rats, Sprague-Dawley
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • SOXB1 Transcription Factors
  • Transcription Factors
  • homeobox protein PITX3
  • Dopamine