title: Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease.
abstract: Parkinson disease (PD) involves the selective loss of midbrain dopamine (mDA) neurons and is a possible target disease for stem cell-based therapy. Human induced pluripotent stem cells (hiPSCs) are a potentially unlimited source of patient-specific cells for transplantation. However, it is critical to evaluate the safety of hiPSCs generated by different reprogramming methods. Here, we compared multiple hiPSC lines derived by virus- and protein-based reprogramming to human ES cells (hESCs). Neuronal precursor cells (NPCs) and dopamine (DA) neurons delivered from lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes, but those cells derived from retrovirus- and protein-based hiPSCs did not. Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging, which was preceded by abrupt induction of p53. In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence. DA neurons derived from protein-based hiPSCs exhibited gene expression, physiological, and electrophysiological properties similar to those of mDA neurons. Transplantation of these cells into rats with striatal lesions, a model of PD, significantly rescued motor deficits. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of PD.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Ko
authors.forename: Mi-Yoon
authors.initials: MY
authors.lastname: Chang
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Yi
authors.forename: Dohoon
authors.initials: D
authors.lastname: Kim
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shim
authors.forename: A-Young
authors.initials: AY
authors.lastname: Jo
authors.forename: Byung-Woo
authors.initials: BW
authors.lastname: Kim
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Lee
authors.forename: Suk-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: Hyun-Chul
authors.initials: HC
authors.lastname: Koh
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine; D002454:Cell Differentiation; D002460:Cell Line / Q000637:transplantation; D019070:Cell Lineage; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D004298:Dopamine / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D016158:Genes, p53; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology* / Q000637:transplantation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D016086:Lentivirus / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000601:surgery*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D051381:Rats; D012190:Retroviridae / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D004298:Dopamine