A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants
(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
- 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 and Björklund, Tomas LU
- organization
-
- Human Neural Developmental Biology (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Molecular Neuromodulation (research group)
- Developmental and Regenerative Neurobiology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Medical Microspectroscopy (research group)
- Behavioural Neuroscience Laboratory (research group)
- publishing date
- 2022-01-11
- 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
- 2024-10-06 07:37:20
@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}}, }