A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants.
Biomarkers
Cell Differentiation
Cell Tracking
Dopaminergic Neurons
/ cytology
Gene Expression
Genes, Reporter
Guanine Nucleotide Exchange Factors
/ genetics
Human Embryonic Stem Cells
/ cytology
Humans
Mesencephalon
/ metabolism
Phenotype
Protein Serine-Threonine Kinases
/ genetics
Stem Cell Transplantation
Synapses
/ metabolism
AAV-MNM008
Cell replacement
Parkinson's disease
animal model
capcid engineering
circuit mapping
dopamine neurons
human embryonic stem cells
monosynaptic tracing
retrograde transport
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
11 01 2022
11 01 2022
Historique:
received:
20
06
2021
revised:
25
11
2021
accepted:
26
11
2021
pubmed:
1
1
2022
medline:
22
3
2022
entrez:
31
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34971563
pii: S2213-6711(21)00595-6
doi: 10.1016/j.stemcr.2021.11.014
pmc: PMC8758947
pii:
doi:
Substances chimiques
Biomarkers
0
Guanine Nucleotide Exchange Factors
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
TRIO protein, human
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
159-172Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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