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AMCoR:Asahikawa Medical University Collection and Research (旭川医科大学学術成果リポジトリ)は、本学で生産された電子的な知的生産物(学術雑誌論文の原稿・教材・学術資料など)を保存し、原則的に無償で発信するためのインターネット上の保管庫です。

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閲覧数:418
ID 20200325_K541
アイテムタイプ Article
このアイテムを表示する
本文 K541 Horikoshi Yuichi_TD.pdf
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Size : 11.5 MB
Last updated : Apr 23, 2021
Downloads : 110

Total downloads since Apr 23, 2021 : 110
タイトル Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes (iPS細胞由来心筋細胞は、脂肪酸処理によって成熟心筋細胞様のエネルギー代謝へ変化する)
著者
堀越, 佑一 (Horikoshi, Yuichi)
上位タイトル
Cells Vol.8, No.9  (2019. 9) ,p.1095-
識別番号
ISSN
2073-4409
DOI 10.3390/cells8091095
その他
PMID: 31533262
博士論文情報
学位授与番号 10107A541
学位授与年月日 2020-03-25
学位名 博士(医学)
学位授与機関 旭川医科大学
抄録 Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. As an example, glycolysis is a major energy source for immature CMs. As CMs mature, the mitochondrial oxidative capacity increases, with fatty acid β-oxidation becoming a key energy source to meet the heart's high energy demand. The immaturity of iPSC-CMs thereby limits their applications. The aim of this study was to investigate whether the energy substrate fatty acid-treated iPSC-CMs exhibit adult CM-like metabolic properties. After 20 days of differentiation from human iPSCs, iPSC-CMs were sequentially cultured with CM purification medium (lactate+/glucose-) for 7 days and maturation medium (fatty acids+/glucose-) for 3-7 days by mimicking the adult CM's preference of utilizing fatty acids as a major metabolic substrate. The purity and maturity of iPSC-CMs were characterized via the analysis of: (1) Expression of CM-specific markers (e.g., troponin T, and sodium and potassium channels) using RT-qPCR, Western blot or immunofluorescence staining and electron microscopy imaging; and (2) cell energy metabolic profiles using the XF96 Extracellular Flux Analyzer. iPSCs-CMs (98% purity) cultured in maturation medium exhibited enhanced elongation, increased mitochondrial numbers with more aligned Z-lines, and increased expression of matured CM-related genes, suggesting that fatty acid-contained medium promotes iPSC-CMs to undergo maturation. In addition, the oxygen consumption rate (OCR) linked to basal respiration, ATP production, and maximal respiration and spare respiratory capacity (representing mitochondrial function) was increased in matured iPSC-CMs. Mature iPSC-CMs also displayed a larger change in basal and maximum respirations due to the utilization of exogenous fatty acids (palmitate) compared with non-matured control iPSC-CMs. Etomoxir (a carnitine palmitoyltransferase 1 inhibitor) but not 2-deoxyglucose (an inhibitor of glycolysis) abolished the palmitate pretreatment-mediated OCR increases in mature iPSC-CMs. Collectively, our data demonstrate for the first time that fatty acid treatment promotes metabolic maturation of iPSC-CMs (as evidenced by enhanced mitochondrial oxidative function and strong capacity of utilizing fatty acids as energy source). These matured iPSC-CMs might be a promising human CM source for broad biomedical application.
キーワード
cardiomyocytes
induced pluripotent stem cells
maturation
metabolism
言語
eng
資源タイプ application/pdf
ジャンル Thesis or Dissertation
著者版フラグ ETD
Index
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/ Public / 学位論文 / 博士論文2020.3~
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