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Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats

Cardoso, Tiago LU ; Adler, Andrew F. LU ; Mattsson, Bengt LU ; Hoban, Deirdre B. LU ; Nolbrant, Sara LU ; Wahlestedt, Jenny Nelander LU ; Kirkeby, Agnete LU ; Grealish, Shane LU ; Björklund, Anders LU and Parmar, Malin LU (2018) In Journal of Comparative Neurology 526(13). p.2133-2146
Abstract

Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18, and 24weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for... (More)

Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18, and 24weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies-based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24weeks. The timing and extent of graft-derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine-induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC-derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC-derived DA neurons to the midbrain.

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published
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keywords
Cell transplantation, Dopaminergic neurons, Human embryonic stem cells, Parkinson's disease, Rabies-based tracing, RRID: AB_10807945, RRID: AB_11034569, RRID: AB_1141717, RRID: AB_177511, RRID: AB_2333092, RRID: AB_300798, RRID: AB_390204, RRID: AB_572263, RRID: AB_627128
in
Journal of Comparative Neurology
volume
526
issue
13
pages
2133 - 2146
publisher
John Wiley & Sons
external identifiers
  • scopus:85051177037
ISSN
0021-9967
DOI
10.1002/cne.24500
language
English
LU publication?
yes
id
411fd0d1-06f2-4567-9fd3-3cc2b39c21da
date added to LUP
2018-09-12 12:19:48
date last changed
2019-04-13 02:17:06
@article{411fd0d1-06f2-4567-9fd3-3cc2b39c21da,
  abstract     = {<p>Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18, and 24weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies-based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24weeks. The timing and extent of graft-derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine-induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC-derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC-derived DA neurons to the midbrain.</p>},
  author       = {Cardoso, Tiago and Adler, Andrew F. and Mattsson, Bengt and Hoban, Deirdre B. and Nolbrant, Sara and Wahlestedt, Jenny Nelander and Kirkeby, Agnete and Grealish, Shane and Björklund, Anders and Parmar, Malin},
  issn         = {0021-9967},
  keyword      = {Cell transplantation,Dopaminergic neurons,Human embryonic stem cells,Parkinson's disease,Rabies-based tracing,RRID: AB_10807945,RRID: AB_11034569,RRID: AB_1141717,RRID: AB_177511,RRID: AB_2333092,RRID: AB_300798,RRID: AB_390204,RRID: AB_572263,RRID: AB_627128},
  language     = {eng},
  month        = {07},
  number       = {13},
  pages        = {2133--2146},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Comparative Neurology},
  title        = {Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats},
  url          = {http://dx.doi.org/10.1002/cne.24500},
  volume       = {526},
  year         = {2018},
}