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A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells

Moriarty, Niamh ; Gantner, Carlos W. ; Hunt, Cameron P.J. ; Ermine, Charlotte M. ; Frausin, Stefano ; Viventi, Serena ; Ovchinnikov, Dmitry A. ; Kirik, Deniz LU ; Parish, Clare L. and Thompson, Lachlan H. LU (2022) In Cell Stem Cell 29(3). p.5-448
Abstract

Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also... (More)

Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
axon growth, cell therapy, GDNF, neural transplantation, neurotrophic, Parkinson's disease, PITX3, regeneration, retrograde tracing, substantia nigra
in
Cell Stem Cell
volume
29
issue
3
pages
5 - 448
publisher
Cell Press
external identifiers
  • scopus:85125220684
  • pmid:35180398
ISSN
1934-5909
DOI
10.1016/j.stem.2022.01.013
language
English
LU publication?
yes
id
0aa9fad2-c532-4aee-a66c-f0b706db543d
date added to LUP
2022-04-26 11:10:02
date last changed
2024-07-11 14:36:14
@article{0aa9fad2-c532-4aee-a66c-f0b706db543d,
  abstract     = {{<p>Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.</p>}},
  author       = {{Moriarty, Niamh and Gantner, Carlos W. and Hunt, Cameron P.J. and Ermine, Charlotte M. and Frausin, Stefano and Viventi, Serena and Ovchinnikov, Dmitry A. and Kirik, Deniz and Parish, Clare L. and Thompson, Lachlan H.}},
  issn         = {{1934-5909}},
  keywords     = {{axon growth; cell therapy; GDNF; neural transplantation; neurotrophic; Parkinson's disease; PITX3; regeneration; retrograde tracing; substantia nigra}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{5--448}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2022.01.013}},
  doi          = {{10.1016/j.stem.2022.01.013}},
  volume       = {{29}},
  year         = {{2022}},
}