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

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

Author information

1
Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Human Neural Development, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: agnete.kirkeby@med.lu.se.
2
Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
3
Department of Cell and Molecular Biology and Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm Branch, 171 77 Stockholm, Sweden.
4
Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, South Wales, UK.
5
Human Neural Development, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
6
Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: malin.parmar@med.lu.se.

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 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

Comment in

PMID:
28094017
PMCID:
PMC5222722
DOI:
10.1016/j.stem.2016.09.004
[Indexed for MEDLINE]
Free PMC Article

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