Journal
EXPERIMENTAL CELL RESEARCH
Volume 318, Issue 19, Pages 2446-2459Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2012.07.018
Keywords
Substantia nigra precursors; Floor plate; Neuron maturation; Bcl-X-L; Neural development; Parkinson's disease cell therapy
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Funding
- Ramon y Cajal programme
- EU [NMP-SL-2008-214706 EXCELL]
- MCyT [SAF2004-03405]
- MICINN/MINECO [BIO2007-66807, PLE2009-0101, SAF2010-17167]
- Carlos III Institute of Health [RD06/0010/0009]
- La Caixa Foundation [BM05-22-0]
- Foundation Ramon Areces
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Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVM1 model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and pro-dopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-X-L induces an increase in the expression of key developmental genes (MSX1, NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (EN1, LMX1B, NURR1 and PITX3). As a result, Bcl-X-L anticipates and enhances DAn generation. (C) 2012 Elsevier Inc. All rights reserved.
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