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

Carlos W. Gantner; Isabelle R. de Luzy; Jessica A. Kauhausen; Niamh Moriarty; Jonathan C. Niclis; Christopher R. Bye; Vanessa Penna; Cameron P.J. Hunt; Charlotte M. Ermine; Colin W. Pouton; Deniz Kirik; Lachlan H. Thompson; Clare L. Parish

doi:10.1016/j.stem.2020.01.010

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

Carlos W. Gantner, Isabelle R. de Luzy, Jessica A. Kauhausen, Niamh Moriarty, Jonathan C. Niclis, Christopher R. Bye, Vanessa Penna, Cameron P.J. Hunt, Charlotte M. Ermine, Colin W. Pouton, Deniz Kirik, Lachlan H. Thompson, Clare L. Parish

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

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.

Originalspråk	engelska
Sidor (från-till)	511-526.e5
Tidskrift	Cell Stem Cell
Volym	26
Nummer	4
DOI	https://doi.org/10.1016/j.stem.2020.01.010
Status	Published - 2020

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Gantner, C. W., de Luzy, I. R., Kauhausen, J. A., Moriarty, N., Niclis, J. C., Bye, C. R., Penna, V., Hunt, C. P. J., Ermine, C. M., Pouton, C. W., Kirik, D., Thompson, L. H., & Parish, C. L. (2020). Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease. Cell Stem Cell, 26(4), 511-526.e5. https://doi.org/10.1016/j.stem.2020.01.010

@article{63bb6cbc42f740e7b0730c1976a2d440,

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

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 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.",

keywords = "dopamine, GDNF, glial cell line-derived neurotrophic factor, graft integration, human embryonic stem cells, LMX1A, neural plasticity, Parkinson's disease, PITX3, transplantation",

author = "Gantner, {Carlos W.} and {de Luzy}, {Isabelle R.} and Kauhausen, {Jessica A.} and Niamh Moriarty and Niclis, {Jonathan C.} and Bye, {Christopher R.} and Vanessa Penna and Hunt, {Cameron P.J.} and Ermine, {Charlotte M.} and Pouton, {Colin W.} and Deniz Kirik and Thompson, {Lachlan H.} and Parish, {Clare L.}",

year = "2020",

doi = "10.1016/j.stem.2020.01.010",

language = "English",

volume = "26",

pages = "511--526.e5",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

AU - Gantner, Carlos W.

AU - de Luzy, Isabelle R.

AU - Kauhausen, Jessica A.

AU - Moriarty, Niamh

AU - Niclis, Jonathan C.

AU - Bye, Christopher R.

AU - Penna, Vanessa

AU - Hunt, Cameron P.J.

AU - Ermine, Charlotte M.

AU - Pouton, Colin W.

AU - Kirik, Deniz

AU - Thompson, Lachlan H.

AU - Parish, Clare L.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - dopamine

KW - GDNF

KW - glial cell line-derived neurotrophic factor

KW - graft integration

KW - human embryonic stem cells

KW - LMX1A

KW - neural plasticity

KW - Parkinson's disease

KW - PITX3

KW - transplantation

U2 - 10.1016/j.stem.2020.01.010

DO - 10.1016/j.stem.2020.01.010

M3 - Article

C2 - 32059808

AN - SCOPUS:85083041485

SN - 1934-5909

VL - 26

SP - 511-526.e5

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

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

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Ämnesklassifikation (UKÄ)

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