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Monosynaptic Tracing using Modified Rabies Virus Reveals Early and Extensive Circuit Integration of Human Embryonic Stem Cell-Derived Neurons.

Abstract
Human embryonic stem cell (hESC)-derived dopamine neurons are currently moving toward clinical use for Parkinson's disease (PD). However, the timing and extent at which stem cell-derived neurons functionally integrate into existing host neural circuitry after transplantation remain largely unknown. In this study, we use modified rabies virus to trace afferent and efferent connectivity of transplanted hESC-derived neurons in a rat model of PD and report that grafted human neurons integrate into the host neural circuitry in an unexpectedly rapid and extensive manner. The pattern of connectivity resembled that of local endogenous neurons, while ectopic connections were not detected. Revealing circuit integration of human dopamine neurons substantiates their potential use in clinical trials. Additionally, our data present rabies-based tracing as a valuable and widely applicable tool for analyzing graft connectivity that can easily be adapted to analyze connectivity of a variety of different neuronal sources and subtypes in different disease models.
AuthorsShane Grealish, Andreas Heuer, Tiago Cardoso, Agnete Kirkeby, Marie Jönsson, Jenny Johansson, Anders Björklund, Johan Jakobsson, Malin Parmar
JournalStem cell reports (Stem Cell Reports) Vol. 4 Issue 6 Pg. 975-83 (Jun 09 2015) ISSN: 2213-6711 [Electronic] United States
PMID26004633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Histones
  • Green Fluorescent Proteins
Topics
  • Animals
  • Cell Differentiation
  • Cell Tracking (methods)
  • Disease Models, Animal
  • Dopaminergic Neurons (cytology, metabolism, transplantation)
  • Female
  • Flow Cytometry
  • Genetic Vectors (genetics, metabolism)
  • Green Fluorescent Proteins (genetics)
  • Histones (genetics)
  • Human Embryonic Stem Cells (cytology)
  • Humans
  • Immunohistochemistry
  • Microscopy, Confocal
  • Parkinson Disease (pathology, therapy)
  • Rabies virus (genetics, physiology)
  • Rats
  • Rats, Nude
  • Rats, Sprague-Dawley
  • Virus Integration (physiology)

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