title: Activin A directs striatal projection neuron differentiation of human pluripotent stem cells.
abstract: The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.
authors: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors: Charles
authors: C
authors: Arber
authors: Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
authors: Sophie V
authors: SV
authors: Precious
authors: National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors: Serafí
authors: S
authors: Cambray
authors: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors: Jessica R
authors: JR
authors: Risner-Janiczek
authors: Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
authors: Claire
authors: C
authors: Kelly
authors: Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, Cardiff CF24 4HQ, UK.
authors: Zoe
authors: Z
authors: Noakes
authors: Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, Cardiff CF24 4HQ, UK.
authors: Marija
authors: M
authors: Fjodorova
authors: Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
authors: Andreas
authors: A
authors: Heuer
authors: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors: Mark A
authors: MA
authors: Ungless
authors: National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors: Tristan A
authors: TA
authors: Rodríguez
authors: Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
authors: Anne E
authors: AE
authors: Rosser
authors: Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
authors: Stephen B
authors: SB
authors: Dunnett
authors: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, Cardiff CF24 4HQ, UK lim26@cf.ac.uk.
authors: Meng
authors: M
authors: Li
mesh_terms: D028341:Activins / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059330:GABAergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005724:Ganglia / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000628:therapy; D017072:Neostriatum / Q000166:cytology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C000596384:BCL11B protein, rat; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D053823:Hedgehog Proteins; C497930:Ppp1r1b protein, rat; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C422405:activin A; D028341:Activins
keywords: Activin; DARPP32 (PPP1R1B); Huntington's disease; Lateral ganglionic eminence; Medium spiny neuron; Neural differentiation; Pluripotent stem cell; Striatum; Transplantation