Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons
Copyright policy )Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons
Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons, and their degeneration underlies some of the clinical features of Huntington’s disease. Using knowledge of human developmental biology and exposure to key neurodevelopmental molecules, human pluripotent stem (hPS) cells were induced to differentiate into MSNs. In a feeder-free adherent culture, ventral telencephalic specification is induced by BMP/TGFβ inhibition and subsequent SHH/DKK1 treatment. The emerging FOXG1+/GSX2+ telencephalic progenitors are then terminally differentiated, resulting in the systematic line-independent generation of FOXP1+/FOXP2+/CTIP2+/calbindin+/DARPP-32+ MSNs. Similar to mature MSNs, these neurons carry dopamine and A2a receptors, elicit a typical firing pattern and show inhibitory postsynaptic currents, as well as dopamine neuromodulation and synaptic integration ability in vivo. When transplanted into the striatum of quinolinic acid-lesioned rats, hPS-derived neurons survive and differentiate into DARPP-32+ neurons, leading to a restoration of apomorphine-induced rotation behavior. In summary, hPS cells can be efficiently driven to acquire a functional striatal fate using an ontogeny-recapitulating stepwise method that represents a platform for in vitro human developmental neurobiology studies and drug screening approaches.
- Cardiff University United Kingdom
- University of Milan Italy
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE United Kingdom
- University of Pisa Italy
- University of Cambridge United Kingdom
Pluripotent Stem Cells, 570, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation, Dopamine and cAMP-Regulated Phosphoprotein 32, Patch-Clamp Techniques, Cell Survival, Cell Transplantation, 610, Mice, Cell Adhesion, Animals, Humans, Cell Lineage, GABAergic Neurons, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation; Animals; Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Survival; Cell Transplantation; Dopamine and cAMP-Regulated Phosphoprotein 32; Embryonic Stem Cells; Female; Fibroblasts; Flow Cytometry; GABAergic Neurons; Humans; Huntington Disease; Mice; Neurons; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Pluripotent Stem Cells; Quinolinic Acid; RNA; Rats; Stem Cells; Time Factors; Developmental Biology; Molecular Biology, Embryonic Stem Cells, Oligonucleotide Array Sequence Analysis, Neurons, Cell Differentiation, Fibroblasts, Quinolinic Acid, Flow Cytometry, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation; Animals; Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Survival; Cell Transplantation; Dopamine and cAMP-Regulated Phosphoprotein 32; Embryonic Stem Cells; Female; Fibroblasts; Flow Cytometry; GABAergic Neurons; Humans; Huntington Disease; Mice; Neurons; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Pluripotent Stem Cells; Quinolinic Acid; RNA; Rats; Stem Cells; Time Factors; Molecular Biology; Developmental Biology, Huntington Disease, Female
Pluripotent Stem Cells, 570, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation, Dopamine and cAMP-Regulated Phosphoprotein 32, Patch-Clamp Techniques, Cell Survival, Cell Transplantation, 610, Mice, Cell Adhesion, Animals, Humans, Cell Lineage, GABAergic Neurons, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation; Animals; Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Survival; Cell Transplantation; Dopamine and cAMP-Regulated Phosphoprotein 32; Embryonic Stem Cells; Female; Fibroblasts; Flow Cytometry; GABAergic Neurons; Humans; Huntington Disease; Mice; Neurons; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Pluripotent Stem Cells; Quinolinic Acid; RNA; Rats; Stem Cells; Time Factors; Developmental Biology; Molecular Biology, Embryonic Stem Cells, Oligonucleotide Array Sequence Analysis, Neurons, Cell Differentiation, Fibroblasts, Quinolinic Acid, Flow Cytometry, DARPP-32 (PPP1R1B); Directed differentiation; Human embryonic stem cells; Huntington's disease; Medium spiny neurons; Striatal neuronal differentiation; Animals; Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Survival; Cell Transplantation; Dopamine and cAMP-Regulated Phosphoprotein 32; Embryonic Stem Cells; Female; Fibroblasts; Flow Cytometry; GABAergic Neurons; Humans; Huntington Disease; Mice; Neurons; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Pluripotent Stem Cells; Quinolinic Acid; RNA; Rats; Stem Cells; Time Factors; Molecular Biology; Developmental Biology, Huntington Disease, Female
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).160 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!