Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease

Cell Stem Cell. 2017 Jan 5;20(1):135-148. doi: 10.1016/j.stem.2016.09.004. Epub 2016 Oct 27.


Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors. We found that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs.

Keywords: FGF8; GMP; MHB; Parkinson’s disease; STN; VM; diencephalon; dopaminergic neurons; good manufacturing practice; hESCs; human embryonic stem cells; midbrain-hindbrain boundary; subthalamic nucleus; transplantation; ventral midbrain.

MeSH terms

  • Animals
  • Biomarkers / metabolism*
  • Cell Differentiation* / drug effects
  • Cell Lineage / drug effects
  • Cells, Cultured
  • Dopamine / metabolism
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Female
  • Fibroblast Growth Factor 8 / metabolism
  • Human Embryonic Stem Cells / cytology*
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / transplantation*
  • Humans
  • Laminin / pharmacology
  • Mesencephalon / metabolism
  • Parkinson Disease / therapy*
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Sequence Analysis, RNA
  • Stem Cell Transplantation*
  • Subthalamic Nucleus / cytology
  • Subthalamic Nucleus / metabolism
  • Time Factors
  • Translational Research, Biomedical*
  • Treatment Outcome


  • Biomarkers
  • Laminin
  • Fibroblast Growth Factor 8
  • Dopamine