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

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. [Display omitted] •Common markers of hESC-derived DA progenitors correlate poorly with graft outcome•RNA-seq reveals correlation of caudal midbrain markers with DA neuron yield in vivo•Staged application of FGF8b patterns hESC-derived progenitors to a caudal VM fate•GMP adaptation of differentiation using this approach improves transplant outcome Kirkeby et al. show that identification and application of a set of predictive markers can help refine differentiation protocols and improve transplant outcome in a preclinical model for hESC-based treatment of Parkinson’s disease.