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

TY - JOUR

T1 - Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.

AU - Kirkeby, Agnete

AU - Nolbrant, Sara

AU - Tiklova, Katarina

AU - Heuer, Andreas

AU - Kee, Nigel

AU - Cardoso, Tiago

AU - Ottosson, Daniella Rylander

AU - Lelos, Mariah J.

AU - Rifes, Pedro

AU - Dunnett, Stephen B.

AU - Grealish, Shane

AU - Perlmann, Thomas

AU - Parmar, Malin.

N1 - M1 - Copyright (C) 2018 American Chemical Society (ACS). All Rights Reserved. CAPLUS AN 2016:1779232(Journal; Online Computer File)

PY - 2017/1/5

Y1 - 2017/1/5

N2 - 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.

AB - 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.

KW - biomarker cell differentiation hESC transplant Parkinson Disease

U2 - 10.1016/j.stem.2016.09.004

DO - 10.1016/j.stem.2016.09.004

M3 - Journal article

C2 - 28094017

SN - 1934-5909

VL - 20

SP - 135

EP - 148

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -