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

   

Authors:	Steinbeck, J. A.; Choi, S. J.; Mrejeru, A.; Ganat, Y.; Deisseroth, K.; Sulzer, D.; Mosharov, E. V.; Studer, L.
Article Title:	Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model
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. © 2015 Nature America, Inc. All rights reserved.
Keywords:	controlled study; human cell; nonhuman; animal cell; mouse; cytology; animals; animal tissue; mus; cell growth; embryonic stem cell; animal experiment; animal model; neurons; animalia; amines; lentivirus vector; stem cells; mesencephalon; pluripotent stem cells; gene silencing; molecular biology; parkinson disease; electrophysiology; dopamine; dopaminergic nerve cell; diseases; neurology; neurophysiology; cells; recovery; human embryonic stem cells; neural stem cell transplantation; synaptic transmission; parkinson's disease; parkinsonia; brain electrophysiology; human; priority journal; article; dopamine release; apomorphine; grafting (chemical); graft functions; neurological disease; neuronal activities; postmortem analysis; optogenetics
Journal Title:	Nature Biotechnology
Volume:	33
Issue:	2
ISSN:	1087-0156
Publisher:	Nature Publishing Group
Date Published:	2015-02-01
Start Page:	204
End Page:	209
Language:	English
DOI:	10.1038/nbt.3124
PROVIDER:	scopus
PUBMED:	25580598
PMCID:	PMC5117952
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84923294447&partnerID=40&md5=bfcf5082297c298f3d1e0ee96edd9b8f
Notes:	Export Date: 2 April 2015 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/70843