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MalinÅ

Malin Åkerblom

Project manager

MalinÅ

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

Author

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

Summary, in English

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.

Department/s

  • Human Neural Developmental Biology
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Molecular Neuromodulation
  • Developmental and Regenerative Neurobiology
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Medical Microspectroscopy
  • Behavioural Neuroscience Laboratory

Publishing year

2022-01-11

Language

English

Pages

159-172

Publication/Series

Stem Cell Reports

Volume

17

Issue

1

Document type

Journal article

Publisher

Cell Press

Topic

  • Neurosciences

Keywords

  • AAV-MNM008
  • animal model
  • capcid engineering
  • Cell replacement
  • circuit mapping
  • dopamine neurons
  • human embryonic stem cells
  • monosynaptic tracing
  • Parkinson's disease
  • retrograde transport

Status

Published

Research group

  • Human Neural Developmental Biology
  • Molecular Neuromodulation
  • Developmental and Regenerative Neurobiology
  • Medical Microspectroscopy
  • Behavioural Neuroscience Laboratory

ISBN/ISSN/Other

  • ISSN: 2213-6711