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A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants

Aldrin-Kirk, Patrick LU ; Åkerblom, Malin LU ; Cardoso, Tiago LU ; Nolbrant, Sara LU ; Adler, Andrew F. LU ; Liu, Xiaohe LU ; Heuer, Andreas LU ; Davidsson, Marcus LU ; Parmar, Malin LU orcid and Björklund, Tomas LU (2022) In Stem Cell Reports 17(1). p.159-172
Abstract

Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons... (More)

Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV-MNM008, animal model, capcid engineering, Cell replacement, circuit mapping, dopamine neurons, human embryonic stem cells, monosynaptic tracing, Parkinson's disease, retrograde transport
in
Stem Cell Reports
volume
17
issue
1
pages
14 pages
publisher
Cell Press
external identifiers
  • pmid:34971563
  • scopus:85122325493
ISSN
2213-6711
DOI
10.1016/j.stemcr.2021.11.014
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 The Authors
id
b5514399-a08e-440b-a230-33a7cab97ec3
date added to LUP
2022-02-24 15:18:56
date last changed
2024-04-20 14:39:51
@article{b5514399-a08e-440b-a230-33a7cab97ec3,
  abstract     = {{<p>Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.</p>}},
  author       = {{Aldrin-Kirk, Patrick and Åkerblom, Malin and Cardoso, Tiago and Nolbrant, Sara and Adler, Andrew F. and Liu, Xiaohe and Heuer, Andreas and Davidsson, Marcus and Parmar, Malin and Björklund, Tomas}},
  issn         = {{2213-6711}},
  keywords     = {{AAV-MNM008; animal model; capcid engineering; Cell replacement; circuit mapping; dopamine neurons; human embryonic stem cells; monosynaptic tracing; Parkinson's disease; retrograde transport}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{159--172}},
  publisher    = {{Cell Press}},
  series       = {{Stem Cell Reports}},
  title        = {{A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants}},
  url          = {{http://dx.doi.org/10.1016/j.stemcr.2021.11.014}},
  doi          = {{10.1016/j.stemcr.2021.11.014}},
  volume       = {{17}},
  year         = {{2022}},
}