Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 7, Pages E1234-E1242Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1611473114
Keywords
MSNs; Gsx2; Ebf1; hES cells; HD
Categories
Funding
- Marie Curie Reintegration Grant [268248]
- CHDI Foundation [A7333]
- Programmi di Ricerca Scientifica di rilevanza Nazionale Grant [2008JKSHKN_001]
- NeurostemcellRepair Grant [NSCR 602278]
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Medium spiny neurons (MSNs) are a key population in the basal ganglia network, and their degeneration causes a severe neurode-generative disorder, Huntington's disease. Understanding how ventral neuroepithelial progenitors differentiate into MSNs is critical for regenerative medicine to develop specific differentiation protocols using human pluripotent stem cells. Studies performed in murine models have identified some transcriptional determinants, including GS Homeobox 2 (Gsx2) and Early B-cell factor 1 (Ebf1). Here, we have generated human embryonic stem (hES) cell lines inducible for these transcription factors, with the aims of (i) studying their biological role in human neural progenitors and (ii) incorporating TF conditional expression in a developmental-based protocol for generating MSNs from hES cells. Using this approach, we found that Gsx2 delays cell-cycle exit and reduces Pax6 expression, whereas Ebf1 promotes neuronal differentiation. Moreover, we found that Gsx2 and Ebf1 combined overexpression in hES cells achieves high yields of MSNs, expressing Darpp32 and Ctip2, in vitro as well in vivo after transplantation. We show that hES-derived striatal progenitors can be transplanted in animal models and can differentiate and integrate into the host, extending fibers over a long distance.
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