title: Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1.
abstract: For cell transplantation therapy for Parkinson's disease (PD) to be realized, the grafted neurons should be integrated into the host neuronal circuit to restore the lost neuronal function. Here, using wheat-germ agglutinin-based transsynaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons. In addition, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administered rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD.
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kaneyasu
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Doi
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Bumpei
authors.initials: B
authors.lastname: Samata
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Bio-function Imaging Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tahara
authors.affiliation: Bio-function Imaging Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: jbtaka@cira.kyoto-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods; D014183:Transplantation, Heterologous
chemical_list: D039081:Integrin alpha5beta1; D008694:Methamphetamine; D004958:Estradiol; D016627:Oxidopamine
keywords: Parkinson's disease; cell transplantation therapy; estradiol-2-benzoate; integrin α5β1; synaptic formation; transsynaptic tracing