Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Biotechnol. 2015 Feb;33(2):204-9. doi: 10.1038/nbt.3124. Epub 2015 Jan 12.

Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model.

Author information

  • 11] Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York, USA. [2] Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
  • 2Department of Neurology, Columbia University Medical Center, New York, New York, USA.
  • 31] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] Department of Psychiatry, Stanford University, Stanford, California, USA. [3] Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
  • 41] Department of Neurology, Columbia University Medical Center, New York, New York, USA. [2] Department of Psychiatry, Columbia University Medical Center, New York, New York, USA. [3] Department of Pharmacology, Columbia University Medical Center, New York, New York, USA.

Abstract

Recent studies have shown evidence of behavioral recovery after transplantation of human pluripotent stem cell (PSC)-derived neural cells in animal models of neurological disease. However, little is known about the mechanisms underlying graft function. Here we use optogenetics to modulate in real time electrophysiological and neurochemical properties of mesencephalic dopaminergic (mesDA) neurons derived from human embryonic stem cells (hESCs). In mice that had recovered from lesion-induced Parkinsonian motor deficits, light-induced selective silencing of graft activity rapidly and reversibly re-introduced the motor deficits. The re-introduction of motor deficits was prevented by the dopamine agonist apomorphine. These results suggest that functionality depends on graft neuronal activity and dopamine release. Combining optogenetics, slice electrophysiology and pharmacological approaches, we further show that mesDA-rich grafts modulate host glutamatergic synaptic transmission onto striatal medium spiny neurons in a manner reminiscent of endogenous mesDA neurons. Thus, application of optogenetics in cell therapy can link transplantation, animal behavior and postmortem analysis to enable the identification of mechanisms that drive recovery.

PMID:
25580598
PMCID:
PMC5117952
DOI:
10.1038/nbt.3124
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center