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

Kirkeby, Agnete LU ; Nolbrant, Sara LU ; Tiklova, Katarina; Heuer, Andreas LU ; Kee, Nigel; Cardoso, Tiago LU ; Ottosson, Daniella Rylander LU ; Lelos, Mariah J.; Rifes, Pedro LU and Dunnett, Stephen B, et al. (2017) In Cell Stem Cell 20(1). p.135-148
Abstract

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... (More)

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.

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Please use this url to cite or link to this publication:
@article{db0dfda3-3288-42b8-9513-6cb3a6f37582,
  abstract     = {<p>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 &gt;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.</p>},
  author       = {Kirkeby, Agnete and Nolbrant, Sara and Tiklova, Katarina and Heuer, Andreas and Kee, Nigel and Cardoso, Tiago and Ottosson, Daniella Rylander and Lelos, Mariah J. and Rifes, Pedro and Dunnett, Stephen B and Grealish, Shane and Perlmann, Thomas and Parmar, Malin},
  issn         = {1934-5909},
  keyword      = {diencephalon,dopaminergic neurons,FGF8,GMP,good manufacturing practice,hESCs,human embryonic stem cells,MHB,midbrain-hindbrain boundary,Parkinson's disease,STN,subthalamic nucleus,transplantation,ventral midbrain,VM},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {135--148},
  publisher    = {Cell Press},
  series       = {Cell Stem Cell},
  title        = {Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease},
  url          = {http://dx.doi.org/10.1016/j.stem.2016.09.004},
  volume       = {20},
  year         = {2017},
}