Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons

Alessia Delli Carri, Marco Onorati, Mariah J. Lelos, Valentina Castiglioni, Andrea Faedo, Ramesh Menon, Stefano Camnasio, Romina Vuono, Paolo Spaiardi, Francesca Talpo, Mauro Toselli, Gianvito Martino, Roger A. Barker, Stephen B. Dunnett, Gerardo Biella, Elena Cattaneo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)301-312
Number of pages12
JournalDevelopment
Volume140
Issue number2
DOIs
Publication statusPublished - 2013

Keywords

  • DARPP-32 (PPP1R1B)
  • Directed differentiation
  • Human embryonic stem cells
  • Huntington's disease
  • Medium spiny neurons
  • Striatal neuronal differentiation

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

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