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hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease

Adler, Andrew F. LU ; Cardoso, Tiago LU ; Nolbrant, Sara LU ; Mattsson, Bengt LU ; Hoban, Deirdre B. LU ; Jarl, Ulla LU ; Wahlestedt, Jenny Nelander LU ; Grealish, Shane LU ; Björklund, Anders LU and Parmar, Malin LU (2019) In Cell Reports 28(13). p.5-3473
Abstract

Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's... (More)

Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
brain repair, cell replacement therapy, cell transplantation, grafting, monosynaptic tracing, Parkinson's disease, stem cells
in
Cell Reports
volume
28
issue
13
pages
5 - 3473
publisher
Cell Press
external identifiers
  • scopus:85072215148
  • pmid:31553914
ISSN
2211-1247
DOI
10.1016/j.celrep.2019.08.058
language
English
LU publication?
yes
id
d7cc793e-dd63-45ea-a490-cdd90247354e
date added to LUP
2019-09-27 12:56:22
date last changed
2020-07-29 06:02:03
@article{d7cc793e-dd63-45ea-a490-cdd90247354e,
  abstract     = {<p>Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.</p>},
  author       = {Adler, Andrew F. and Cardoso, Tiago and Nolbrant, Sara and Mattsson, Bengt and Hoban, Deirdre B. and Jarl, Ulla and Wahlestedt, Jenny Nelander and Grealish, Shane and Björklund, Anders and Parmar, Malin},
  issn         = {2211-1247},
  language     = {eng},
  month        = {09},
  number       = {13},
  pages        = {5--3473},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease},
  url          = {http://dx.doi.org/10.1016/j.celrep.2019.08.058},
  doi          = {10.1016/j.celrep.2019.08.058},
  volume       = {28},
  year         = {2019},
}