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
-
The Neurodevelopmental Hypothesis of Huntington's Disease.J Huntingtons Dis. 2020;9(3):217-229. doi: 10.3233/JHD-200394. J Huntingtons Dis. 2020. PMID: 32925079 Free PMC article. Review.
-
Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes.Front Neurosci. 2022 Apr 25;16:843794. doi: 10.3389/fnins.2022.843794. eCollection 2022. Front Neurosci. 2022. PMID: 35546872 Free PMC article. Review.
-
Human Pluripotent Stem Cell-Derived Medium Spiny Neuron-like Cells Exhibit Gene Desensitization.Cells. 2022 Apr 21;11(9):1411. doi: 10.3390/cells11091411. Cells. 2022. PMID: 35563715 Free PMC article.
-
Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases.Annu Rev Pharmacol Toxicol. 2016;56:489-510. doi: 10.1146/annurev-pharmtox-010715-103548. Epub 2015 Oct 28. Annu Rev Pharmacol Toxicol. 2016. PMID: 26514199 Free PMC article. Review.
-
Deciphering the Pathophysiological Mechanisms Underpinning Myoclonus Dystonia Using Pluripotent Stem Cell-Derived Cellular Models.Cells. 2024 Sep 10;13(18):1520. doi: 10.3390/cells13181520. Cells. 2024. PMID: 39329704 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources