Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons
- PMID: 23250204
- DOI: 10.1242/dev.084608
Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons
Abstract
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.
Similar articles
-
Activin A directs striatal projection neuron differentiation of human pluripotent stem cells.Development. 2015 Apr 1;142(7):1375-86. doi: 10.1242/dev.117093. Development. 2015. PMID: 25804741 Free PMC article.
-
Human pluripotent stem cell differentiation into authentic striatal projection neurons.Stem Cell Rev Rep. 2013 Aug;9(4):461-74. doi: 10.1007/s12015-013-9441-8. Stem Cell Rev Rep. 2013. PMID: 23625190
-
GABAergic neurons from mouse embryonic stem cells possess functional properties of striatal neurons in vitro, and develop into striatal neurons in vivo in a mouse model of Huntington's disease.Stem Cell Rev Rep. 2012 Jun;8(2):513-31. doi: 10.1007/s12015-011-9290-2. Stem Cell Rev Rep. 2012. PMID: 21720791
-
Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient.Front Cell Neurosci. 2014 Dec 2;8:398. doi: 10.3389/fncel.2014.00398. eCollection 2014. Front Cell Neurosci. 2014. PMID: 25520619 Free PMC article. Review.
-
How to make striatal projection neurons.Neurogenesis (Austin). 2015 Dec 15;2(1):e1100227. doi: 10.1080/23262133.2015.1100227. eCollection 2015. Neurogenesis (Austin). 2015. PMID: 27606330 Free PMC article. Review.
Cited by
-
ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation.Stem Cell Reports. 2016 Oct 11;7(4):693-706. doi: 10.1016/j.stemcr.2016.08.018. Epub 2016 Sep 29. Stem Cell Reports. 2016. PMID: 27693427 Free PMC article.
-
Induction of DARPP-32 by brain-derived neurotrophic factor in striatal neurons in vitro is modified by histone deacetylase inhibitors and Nab2.PLoS One. 2013 Oct 21;8(10):e76842. doi: 10.1371/journal.pone.0076842. eCollection 2013. PLoS One. 2013. PMID: 24204683 Free PMC article.
-
Cell-based therapies for Huntington's disease.Drug Discov Today. 2014 Jul;19(7):980-4. doi: 10.1016/j.drudis.2014.02.012. Epub 2014 Mar 12. Drug Discov Today. 2014. PMID: 24631682 Free PMC article. Review.
-
Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking.Cell Stem Cell. 2016 Feb 4;18(2):174-88. doi: 10.1016/j.stem.2016.01.012. Cell Stem Cell. 2016. PMID: 26849304 Free PMC article. Review.
-
A circular RNA map for human induced pluripotent stem cells of foetal origin.EBioMedicine. 2020 Jul;57:102848. doi: 10.1016/j.ebiom.2020.102848. Epub 2020 Jun 20. EBioMedicine. 2020. PMID: 32574961 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources