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Identification of Transplantable Dopamine Neuron Precursors at Different Stages of Midbrain Neurogenesis.

Jönsson, Marie LU ; Ono, Yuichi ; Björklund, Anders LU orcid and Thompson, Lachlan LU (2009) In Experimental Neurology 219. p.341-354
Abstract
Protocols used for generation of mesencephalic dopamine (mesDA) neurons from stem cells, or fetal brain tissue, invariably result in cell preparations that are highly mixed in composition, containing mesDA neuron precursors in various states of fate commitment and differentiation. For further optimisation and refinement of these procedures it is essential to determine the optimal stage of development and phenotypic characterisics of cells used for grafting. We have used fluorescence-activated cell sorting procedures to isolate mesDA precursors in defined stages of differentiation from mouse ventral mesencephalon (VM), at embryonic day 10.5 (E10.5), when the mesDA neuron domain consists of proliferative radial glia-like cells expressing the... (More)
Protocols used for generation of mesencephalic dopamine (mesDA) neurons from stem cells, or fetal brain tissue, invariably result in cell preparations that are highly mixed in composition, containing mesDA neuron precursors in various states of fate commitment and differentiation. For further optimisation and refinement of these procedures it is essential to determine the optimal stage of development and phenotypic characterisics of cells used for grafting. We have used fluorescence-activated cell sorting procedures to isolate mesDA precursors in defined stages of differentiation from mouse ventral mesencephalon (VM), at embryonic day 10.5 (E10.5), when the mesDA neuron domain consists of proliferative radial glia-like cells expressing the mesDA neuron determinant Lmx1a and the floor-plate marker Corin, and at E12.5, when the VM has expanded to comprise a mixture of proliferative progenitors, neuroblasts and young neurons. The sorted cells were transplanted to the striatum of 6-hydroxydopamine-lesioned rats. Results show that the Lmx1a/Corin-expressing ventricular zone progenitors, which are the source of mesDA neurons in grafts from E10.5 VM, had lost this capacity at E12.5. At this later stage all transplantable mesDA precursors resided in the intermediate zone as postmitotic Nurr1-expressing neuroblasts. The more differentiated, TH-expressing cells survived sorting and transplantation poorly. We also provide evidence that, during early mesDA neurogenesis, the progenitors for nigral mesDA neurons segregate to lateral parts of the Lmx1a-expressing domain and can be selectively isolated based on their level of Corin expression. These results have implications for current efforts to develop well-characterised stem-cell derived mesDA progenitor cell preparations for cell therapy. (Less)
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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Neurology
volume
219
pages
341 - 354
publisher
Elsevier
external identifiers
  • wos:000269398600040
  • pmid:19555687
  • scopus:67849111372
ISSN
0014-4886
DOI
10.1016/j.expneurol.2009.06.006
language
English
LU publication?
yes
id
eb44e5e4-4c9c-434a-98ac-00d240bc85a1 (old id 1433893)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19555687?dopt=Abstract
date added to LUP
2016-04-04 08:54:17
date last changed
2022-04-15 21:02:10
@article{eb44e5e4-4c9c-434a-98ac-00d240bc85a1,
  abstract     = {{Protocols used for generation of mesencephalic dopamine (mesDA) neurons from stem cells, or fetal brain tissue, invariably result in cell preparations that are highly mixed in composition, containing mesDA neuron precursors in various states of fate commitment and differentiation. For further optimisation and refinement of these procedures it is essential to determine the optimal stage of development and phenotypic characterisics of cells used for grafting. We have used fluorescence-activated cell sorting procedures to isolate mesDA precursors in defined stages of differentiation from mouse ventral mesencephalon (VM), at embryonic day 10.5 (E10.5), when the mesDA neuron domain consists of proliferative radial glia-like cells expressing the mesDA neuron determinant Lmx1a and the floor-plate marker Corin, and at E12.5, when the VM has expanded to comprise a mixture of proliferative progenitors, neuroblasts and young neurons. The sorted cells were transplanted to the striatum of 6-hydroxydopamine-lesioned rats. Results show that the Lmx1a/Corin-expressing ventricular zone progenitors, which are the source of mesDA neurons in grafts from E10.5 VM, had lost this capacity at E12.5. At this later stage all transplantable mesDA precursors resided in the intermediate zone as postmitotic Nurr1-expressing neuroblasts. The more differentiated, TH-expressing cells survived sorting and transplantation poorly. We also provide evidence that, during early mesDA neurogenesis, the progenitors for nigral mesDA neurons segregate to lateral parts of the Lmx1a-expressing domain and can be selectively isolated based on their level of Corin expression. These results have implications for current efforts to develop well-characterised stem-cell derived mesDA progenitor cell preparations for cell therapy.}},
  author       = {{Jönsson, Marie and Ono, Yuichi and Björklund, Anders and Thompson, Lachlan}},
  issn         = {{0014-4886}},
  language     = {{eng}},
  pages        = {{341--354}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Neurology}},
  title        = {{Identification of Transplantable Dopamine Neuron Precursors at Different Stages of Midbrain Neurogenesis.}},
  url          = {{http://dx.doi.org/10.1016/j.expneurol.2009.06.006}},
  doi          = {{10.1016/j.expneurol.2009.06.006}},
  volume       = {{219}},
  year         = {{2009}},
}