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 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.
Original language | English |
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Pages (from-to) | 159-172 |
Number of pages | 14 |
Journal | Stem Cell Reports |
Volume | 17 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2022 Jan 11 |
Subject classification (UKÄ)
- Neurosciences
Free keywords
- AAV-MNM008
- animal model
- capcid engineering
- Cell replacement
- circuit mapping
- dopamine neurons
- human embryonic stem cells
- monosynaptic tracing
- Parkinson's disease
- retrograde transport