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Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-X-L

Seiz, Emma G.; Ramos-Gomez, Milagros; Courtois, Elise T.; Tönnesen, Jan LU ; Kokaia, Merab LU ; Liste Noya, Isabel and Martinez-Serrano, Alberto (2012) In Experimental Cell Research 318(19). p.2446-2459
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Substantia nigra precursors, Floor plate, Neuron maturation, Bcl-X-L, Neural development, Parkinson's disease cell therapy
in
Experimental Cell Research
volume
318
issue
19
pages
2446 - 2459
publisher
Academic Press
external identifiers
  • wos:000309303200004
  • scopus:84866328125
ISSN
1090-2422
DOI
10.1016/j.yexcr.2012.07.018
language
English
LU publication?
yes
id
b0e4d0bf-3a96-4d5c-b34c-4f1b748cfe71 (old id 3189556)
date added to LUP
2012-12-03 07:09:16
date last changed
2017-01-08 03:19:46
@article{b0e4d0bf-3a96-4d5c-b34c-4f1b748cfe71,
  abstract     = {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.},
  author       = {Seiz, Emma G. and Ramos-Gomez, Milagros and Courtois, Elise T. and Tönnesen, Jan and Kokaia, Merab and Liste Noya, Isabel and Martinez-Serrano, Alberto},
  issn         = {1090-2422},
  keyword      = {Substantia nigra precursors,Floor plate,Neuron maturation,Bcl-X-L,Neural development,Parkinson's disease cell therapy},
  language     = {eng},
  number       = {19},
  pages        = {2446--2459},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-X-L},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2012.07.018},
  volume       = {318},
  year         = {2012},
}