title: Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation.
abstract: Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson's disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. Here, we show that human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, CORIN. We induced DA neurons using scalable culture conditions on human laminin fragment, and the sorted CORIN(+) cells expressed the midbrain DA progenitor markers, FOXA2 and LMX1A. When transplanted into 6-OHDA-lesioned rats, the CORIN(+) cells survived and differentiated into midbrain DA neurons in vivo, resulting in significant improvement of the motor behavior, without tumor formation. In particular, the CORIN(+) cells in a NURR1(+) cell-dominant stage exhibited the best survival and function as DA neurons. Our method is a favorable strategy in terms of scalability, safety, and efficiency and may be advantageous for clinical application.
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Doi
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Bumpei
authors.initials: B
authors.lastname: Samata
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Katsukawa
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Morizane
authors.affiliation: Group for Neuronal Differentiation and Development, KAN Research Institute, Inc., 650-0047 Kobe, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, 565-0871 Osaka, Japan.
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
authors.affiliation: Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan ; Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, 606-8507 Kyoto, Japan ; Department of Neurosurgery, Kyoto University School of Medicine, 606-8507 Kyoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism; D013997:Time Factors
chemical_list: C119812:CORIN protein, human; D012697:Serine Endopeptidases