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Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment

Ganat, Yosif M.; Calder, Elizabeth L.; Kriks, Sonja; Nelander Wahlestedt, Jenny LU ; Tu, Edmund Y.; Jia, Fan; Battista, Daniela; Harrison, Neil; Parmar, Malin LU and Tomishima, Mark J., et al. (2012) In Journal of Clinical Investigation 122(8). p.2928-2939
Abstract
Embryonic stem cells (ESCs) represent a promising source of midbrain dopaminergic (DA) neurons for applications in Parkinson disease. However, ESC-based transplantation paradigms carry a risk of introducing inappropriate or tumorigenic cells. Cell purification before transplantation may alleviate these concerns and enable identification of the specific DA neuron stage most suitable for cell therapy. Here, we used 3 transgenic mouse ESC reporter lines to mark DA neurons at 3 stages of differentiation (early, middle, and late) following induction of differentiation using Hes5::GFP, Nurr1::GFP, and Pitx3::YFP transgenes, respectively. Transplantation of FACS-purified cells from each line resulted in DA neuron engraftment, with the mid-stage... (More)
Embryonic stem cells (ESCs) represent a promising source of midbrain dopaminergic (DA) neurons for applications in Parkinson disease. However, ESC-based transplantation paradigms carry a risk of introducing inappropriate or tumorigenic cells. Cell purification before transplantation may alleviate these concerns and enable identification of the specific DA neuron stage most suitable for cell therapy. Here, we used 3 transgenic mouse ESC reporter lines to mark DA neurons at 3 stages of differentiation (early, middle, and late) following induction of differentiation using Hes5::GFP, Nurr1::GFP, and Pitx3::YFP transgenes, respectively. Transplantation of FACS-purified cells from each line resulted in DA neuron engraftment, with the mid-stage and late-stage neuron grafts being composed almost exclusively of midbrain DA neurons. Mid-stage neuron cell grafts had the greatest amount of DA neuron survival and robustly induced recovery of motor deficits in hemiparkinsonian mice. Our data suggest that the Nurrl(+) stage (middle stage) of neuronal differentiation is particularly suitable for grafting ESC-derived DA neurons. Moreover, global transcriptome analysis of progeny from each of the ESC reporter lines revealed expression of known midbrain DA neuron genes and also uncovered previously uncharacterized midbrain genes. These data demonstrate remarkable fate specificity of ESC-derived DA neurons and outline a sequential stage-specific ESC reporter line paradigm for in vivo gene discovery. (Less)
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publication status
published
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Journal of Clinical Investigation
volume
122
issue
8
pages
2928 - 2939
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000307128600029
  • scopus:84864767860
ISSN
0021-9738
DOI
10.1172/JCI58767
language
English
LU publication?
yes
id
816bc995-3b85-4635-bb1c-d3657280c078 (old id 3070235)
date added to LUP
2012-10-05 07:12:27
date last changed
2017-10-22 04:24:36
@article{816bc995-3b85-4635-bb1c-d3657280c078,
  abstract     = {Embryonic stem cells (ESCs) represent a promising source of midbrain dopaminergic (DA) neurons for applications in Parkinson disease. However, ESC-based transplantation paradigms carry a risk of introducing inappropriate or tumorigenic cells. Cell purification before transplantation may alleviate these concerns and enable identification of the specific DA neuron stage most suitable for cell therapy. Here, we used 3 transgenic mouse ESC reporter lines to mark DA neurons at 3 stages of differentiation (early, middle, and late) following induction of differentiation using Hes5::GFP, Nurr1::GFP, and Pitx3::YFP transgenes, respectively. Transplantation of FACS-purified cells from each line resulted in DA neuron engraftment, with the mid-stage and late-stage neuron grafts being composed almost exclusively of midbrain DA neurons. Mid-stage neuron cell grafts had the greatest amount of DA neuron survival and robustly induced recovery of motor deficits in hemiparkinsonian mice. Our data suggest that the Nurrl(+) stage (middle stage) of neuronal differentiation is particularly suitable for grafting ESC-derived DA neurons. Moreover, global transcriptome analysis of progeny from each of the ESC reporter lines revealed expression of known midbrain DA neuron genes and also uncovered previously uncharacterized midbrain genes. These data demonstrate remarkable fate specificity of ESC-derived DA neurons and outline a sequential stage-specific ESC reporter line paradigm for in vivo gene discovery.},
  author       = {Ganat, Yosif M. and Calder, Elizabeth L. and Kriks, Sonja and Nelander Wahlestedt, Jenny and Tu, Edmund Y. and Jia, Fan and Battista, Daniela and Harrison, Neil and Parmar, Malin and Tomishima, Mark J. and Rutishauser, Urs and Studer, Lorenz},
  issn         = {0021-9738},
  language     = {eng},
  number       = {8},
  pages        = {2928--2939},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment},
  url          = {http://dx.doi.org/10.1172/JCI58767},
  volume       = {122},
  year         = {2012},
}