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Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

Gantner, Carlos W. ; de Luzy, Isabelle R. ; Kauhausen, Jessica A. ; Moriarty, Niamh ; Niclis, Jonathan C. ; Bye, Christopher R. ; Penna, Vanessa ; Hunt, Cameron P.J. ; Ermine, Charlotte M. and Pouton, Colin W. , et al. (2020) In Cell Stem Cell 26(4). p.5-526
Abstract

Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD... (More)

Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
dopamine, GDNF, glial cell line-derived neurotrophic factor, graft integration, human embryonic stem cells, LMX1A, neural plasticity, Parkinson's disease, PITX3, transplantation
in
Cell Stem Cell
volume
26
issue
4
pages
5 - 526
publisher
Cell Press
external identifiers
  • pmid:32059808
  • scopus:85083041485
ISSN
1934-5909
DOI
10.1016/j.stem.2020.01.010
language
English
LU publication?
yes
id
63bb6cbc-42f7-40e7-b073-0c1976a2d440
date added to LUP
2020-05-07 11:52:15
date last changed
2024-11-15 06:16:30
@article{63bb6cbc-42f7-40e7-b073-0c1976a2d440,
  abstract     = {{<p>Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.</p>}},
  author       = {{Gantner, Carlos W. and de Luzy, Isabelle R. and Kauhausen, Jessica A. and Moriarty, Niamh and Niclis, Jonathan C. and Bye, Christopher R. and Penna, Vanessa and Hunt, Cameron P.J. and Ermine, Charlotte M. and Pouton, Colin W. and Kirik, Deniz and Thompson, Lachlan H. and Parish, Clare L.}},
  issn         = {{1934-5909}},
  keywords     = {{dopamine; GDNF; glial cell line-derived neurotrophic factor; graft integration; human embryonic stem cells; LMX1A; neural plasticity; Parkinson's disease; PITX3; transplantation}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{5--526}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2020.01.010}},
  doi          = {{10.1016/j.stem.2020.01.010}},
  volume       = {{26}},
  year         = {{2020}},
}