title: Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.
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.
authors.affiliation: 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.
authors.forename: Agnete
authors.initials: A
authors.lastname: Kirkeby
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Nolbrant
authors.affiliation: Department of Cell and Molecular Biology and Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm Branch, 171 77 Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Tiklova
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heuer
authors.affiliation: Department of Cell and Molecular Biology and Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm Branch, 171 77 Stockholm, Sweden.
authors.forename: Nigel
authors.initials: N
authors.lastname: Kee
authors.affiliation: 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.
authors.forename: Tiago
authors.initials: T
authors.lastname: Cardoso
authors.affiliation: 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.
authors.forename: Daniella Rylander
authors.initials: DR
authors.lastname: Ottosson
authors.affiliation: Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, South Wales, UK.
authors.forename: Mariah J
authors.initials: MJ
authors.lastname: Lelos
authors.affiliation: 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.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rifes
authors.affiliation: Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, South Wales, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Dunnett
authors.affiliation: 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.
authors.forename: Shane
authors.initials: S
authors.lastname: Grealish
authors.affiliation: Department of Cell and Molecular Biology and Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm Branch, 171 77 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
authors.affiliation: 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.
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation*; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008636:Mesencephalon / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy*; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D033581:Stem Cell Transplantation; D020531:Subthalamic Nucleus / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007797:Laminin; D051524:Fibroblast Growth Factor 8; D004298:Dopamine
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