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

Patrick Aldrin-Kirk, Malin Åkerblom, Tiago Cardoso, Sara Nolbrant, Andrew F. Adler, Xiaohe Liu, Andreas Heuer, Marcus Davidsson, Malin Parmar, Tomas Björklund

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)159-172
Number of pages14
JournalStem Cell Reports
Volume17
Issue number1
DOIs
Publication statusPublished - 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

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