A Novel Two-factor Monosynaptic TRIO Tracing Method for Assessment of Circuit Integration of HESC-derived Dopamine Transplants

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2021 Dec 31

PMID 34971563

Citations 4

Authors

Patrick Aldrin-Kirk

Malin Akerblom

Tiago Cardoso

Sara Nolbrant

Andrew F Adler

Xiaohe Liu

Andreas Heuer

Marcus Davidsson

Malin Parmar

Tomas Bjorklund

Affiliations

Soon will be listed here.

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.

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