GENERAZIONE DI NEURONI STRIATALI FUNZIONALI DA CELLULE STAMINALI EMBRIONALI UMANE.
Tesi di Dottorato
Data di Pubblicazione:
2013
Citazione:
GENERAZIONE DI NEURONI STRIATALI FUNZIONALI DA CELLULE STAMINALI EMBRIONALI UMANE / A. Delli Carri ; tutor: E. Cattaneo ; coordinatore: G. Franceschini. UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Jan 18. 25. ciclo, Anno Accademico 2012. [10.13130/delli-carri-alessia_phd2013-01-18].
Abstract:
Medium-sized spiny neurons (MSNs) are the only neostriatum-projection neurons, and their degeneration underlies some of clinical features of Huntington's disease. We used human developmental biology and exposure to key neurodevelopmental molecules to drive human pluripotent stem (hPS) cells into MSNs. In a feeder-free adherent culture, ventral-telencephalic specification is induced by BMP/TGF-β inhibition and subsequent SHH/DKK-1 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. Similarly to mature MSNs, these neurons carry dopamine- and A2a-receptors, elicit 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 behaviour. In summary, hPS cells can be efficiently
driven to acquire a functional striatal fate using an ontogeny-recapitulating stepwise method. Moreover, we have established stable HD-iPS cell lines that recapitulating, in vitro, features of the disease can be used for investigating disease mechanisms that underlie HD, representing a platform for in vitro human developmental neurobiology studies and drug screening approaches.
Tipologia IRIS:
Tesi di dottorato
Keywords:
striatum ; medium sized spiny neurons ; embryonic stem cells ; induced pluripotent stem cells ; huntington's disease
Elenco autori:
A. DELLI CARRI
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