Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery.
Daniel Tornero,Somsak Wattananit,Marita Grönning Madsen,Philipp Koch,James Wood,Jemal Tatarishvili,Yutaka Mine,Ruimin Ge,Emanuela Monni,Karthikeyan Devaraju,Robert F. Hevner,Oliver Brüstle,Olle Lindvall,Zaal Kokaia +13 more
TLDR
It is shown, for the first time, that human skin-derived induced pluripotent stem cells can be differentiated to cortical neuronal progenitors, which survive, differentiate to functional neurons and improve neurological outcome after intracortical implantation in a rat stroke model.Abstract:
Stem cell-based approaches to restore function after stroke through replacement of dead neurons require the generation of specific neuronal subtypes. Loss of neurons in the cerebral cortex is a major cause of stroke-induced neurological deficits in adult humans. Reprogramming of adult human somatic cells to induced pluripotent stem cells is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells can be converted to functional cortical neurons that survive and give rise to behavioural recovery after transplantation in the stroke-injured cerebral cortex is not known. We have generated progenitors in vitro, expressing specific cortical markers and giving rise to functional neurons, from long-term self-renewing neuroepithelial-like stem cells, produced from adult human fibroblast-derived induced pluripotent stem cells. At 2 months after transplantation into the stroke-damaged rat cortex, the cortically fated cells showed less proliferation and more efficient conversion to mature neurons with morphological and immunohistochemical characteristics of a cortical phenotype and higher axonal projection density as compared with non-fated cells. Pyramidal morphology and localization of the cells expressing the cortex-specific marker TBR1 in a certain layered pattern provided further evidence supporting the cortical phenotype of the fated, grafted cells, and electrophysiological recordings demonstrated their functionality. Both fated and non-fated cell-transplanted groups showed bilateral recovery of the impaired function in the stepping test compared with vehicle-injected animals. The behavioural improvement at this early time point was most likely not due to neuronal replacement and reconstruction of circuitry. At 5 months after stroke in immunocompromised rats, there was no tumour formation and the grafted cells exhibited electrophysiological properties of mature neurons with evidence of integration in host circuitry. Our findings show, for the first time, that human skin-derived induced pluripotent stem cells can be differentiated to cortical neuronal progenitors, which survive, differentiate to functional neurons and improve neurological outcome after intracortical implantation in a rat stroke model.read more
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Optogenetics enables functional analysis of human embryonic stem cell–derived grafts in a Parkinson's disease model
Julius A. Steinbeck,Se Joon Choi,Ana Mrejeru,Yosif Ganat,Karl Deisseroth,David Sulzer,Eugene V. Mosharov,Lorenz Studer +7 more
TL;DR: Combining optogenetics, slice electrophysiology and pharmacological approaches, it is shown that mesDA-rich grafts modulate host glutamatergic synaptic transmission onto striatal medium spiny neurons in a manner reminiscent of endogenous mesDA neurons.
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Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease
Agnete Kirkeby,Sara Nolbrant,Katarina Tiklova,Andreas Heuer,Nigel Kee,Tiago Cardoso,Daniella Rylander Ottosson,Mariah Jillian Lelos,Pedro Rifes,Stephen B. Dunnett,Shane Grealish,Thomas Perlmann,Malin Parmar +12 more
TL;DR: A specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo are identified and a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs is developed.
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Neuroprotection for ischaemic stroke: Current status and challenges
TL;DR: A review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade.
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Restoring brain function after stroke — bridging the gap between animals and humans
TL;DR: Clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit, which is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke.
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Moving Stem Cells to the Clinic: Potential and Limitations for Brain Repair
TL;DR: Substantial progress has been made in the derivation of disease-relevant human donor cell populations, and cGMP grade cell products are currently being developed for first in human clinical trials in select disorders.
References
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Journal ArticleDOI
Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses
TL;DR: It was found that induction of cortical neuroepithelial stem cells from human ES cells and human iPS cells was dependent on retinoid signaling and human ES cell and iPS cell differentiation to cerebral cortex recapitulated in vivo development to generate all classes of cortical projection neurons in a fixed temporal order.
Journal ArticleDOI
Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex
Stephen Kelly,Tonya M. Bliss,A. K. Shah,Guohua Sun,Michael Ma,W. C. Foo,Joanna Masel,Midori A. Yenari,Irving L. Weissman,Nobuko Uchida,Theo D. Palmer,Gary K. Steinberg +11 more
TL;DR: Transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.
Journal ArticleDOI
A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction.
TL;DR: Using a laser-Doppler flowmeter, it was found that the relative surface blood flow in cerebral cortex decreased to 62, 48, and 18% of baseline respectively after successive ligation of the right middle cerebral artery, and the right and left common carotid arteries.
Journal ArticleDOI
Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test
TL;DR: The experiments reported here evaluate the usefulness of a new “stepping test” to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine lesions of the mesencephalic dopamine (DA) system, and assess the ability of DA- receptor agonists and fetal DA neuron transplants to reverse these deficits.
Journal ArticleDOI
An intrinsic mechanism of corticogenesis from embryonic stem cells
Nicolas Gaspard,Tristan Bouschet,Raphael Hourez,Jordane Dimidschstein,Gilles Naeije,Jelle van den Ameele,Ira Espuny-Camacho,Adèle Herpoel,Lara Passante,Serge N. Schiffmann,Afsaneh Gaillard,Pierre Vanderhaeghen +11 more
TL;DR: It is shown that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons.
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