title: 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.
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Shane
authors.initials: S
authors.lastname: Grealish
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heuer
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Tiago
authors.initials: T
authors.lastname: Cardoso
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Agnete
authors.initials: A
authors.lastname: Kirkeby
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Jönsson
authors.affiliation: Department of Experimental Medical Science, Molecular Neurogenetics, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Lund Stem Cell Center, Lund University, 22184 Lund, Sweden; Department of Experimental Medical Science, Molecular Neurogenetics, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Jakobsson
authors.affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: malin.parmar@med.lu.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D058948:Cell Tracking / Q000379:methods*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006657:Histones / Q000235:genetics; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy; D011820:Rabies virus / Q000235:genetics* / Q000502:physiology; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D016662:Virus Integration / Q000502:physiology
chemical_list: D006657:Histones; D049452:Green Fluorescent Proteins