Characterization of diploid cardiomyocytes in adult mammalian hearts

• Project/Area Number: 18K19545
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Fujio Yasushi 大阪大学, 薬学研究科, 教授 (20359839)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 心筋細胞 / 1細胞解析 / 二倍体心筋細胞 / 心筋細胞増殖

Outline of Final Research Achievements

Heart is composed of various kinds of cells, including cardiomyocytes, vascular endothelial cells, smooth muscle cells and cardiac fibroblasts. Interestingly, mammalian cardiomyocytes are mainly diploid cells at birth; however, the frequency of tetraploid cardiomyocytes increases afterwards. Therefore, adult mammalian cardiomyocytes are not homogenous. Though it was reported that the adult hearts that are abundant in diploid cardiomyocytes exhibit remarkable reparative/regenerative capacity, the difference between diploid and tetraploid cardiomyocytes remains to be elucidated. In the present study, we characterized adult murine cardiomyocytes by using single cell analysis. And we found that diploid cardiomyocytes have tendency to show juvenile nature, compared with tetraploid cells, though there are no clear differences between them.

Academic Significance and Societal Importance of the Research Achievements

社会の高齢化と食生活の過栄養化に伴い、循環器疾患が増加し、その結果、心不全患者も増加している。心不全は、心臓の機能が低下し、息切れや浮腫が生じる予後不良の病態である。心臓の筋肉は、骨格筋と異なり修復再生能が低いため、循環器疾患により傷害を受けても回復しないことが、心不全の原因であると考えられている。本研究の成果は、成体の心筋細胞の中にも幼若な細胞集団が含まれていることを示すものであり、特に、そのような幼若な細胞集団を標的として介入を加えることによる、新たな心不全治療が開発される可能性があることを示唆する。

Research Products

• [Journal Article] β2‐adrenergic stimulation induces interleukin‐6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts (2020)
  • Author(s): Tanaka Shota、Imaeda Atsuki、Matsumoto Kotaro、Maeda Makiko、Obana Masanori、Fujio Yasushi
  • Journal Title: Pharmacology Research & Perspectives Volume: 8 Issue: 2
  • DOI: 10.1002/prp2.590
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells (2020)
  • Author(s): Lin Y, Higashisaka K, Shintani T, Maki A, Hanamuro S, Haga Y, Maeda S, Tsujino H, Nagano K, Fujio Y, Tsutsumi Y
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4748-4748
  • DOI: 10.1038/s41598-020-61727-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] QT/QTc study shows that a novel 5-HT4 receptor partial agonist minesapride has no effect on QT prolongation. (2020)
  • Author(s): Hamatani, T., Noda, N., Takagaki, T., Yodo, Y., Kakuyama, H., Kaji, Y., Fujio, Y.
  • Journal Title: Clin. Pharmacol. Drug Develop Volume: in press Issue: 8 Pages: 938-951
  • DOI: 10.1002/cpdd.778
  • Peer Reviewed
• [Journal Article] Old-Age Onset Progressive Cardiac Contractile Dysfunction in a Patient with Polycystic Kidney Disease Harboring a <i>PKD1</i> Frameshift Mutation (2019)
  • Author(s): Suwa Yoshinobu、Higo Shuichiro、Nakamoto Kei、Sera Fusako、Kunimatsu Suzuka、Masumura Yuki、Kanzaki Machiko、Mizote Isamu、Mizuno Hiroya、Fujio Yasushi、Hikoso Shungo、Sakata Yasushi
  • Journal Title: International Heart Journal Volume: 60 Issue: 1 Pages: 220-225
  • DOI: 10.1536/ihj.18-184
  • NAID: 130007557187
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-01-31
  • Peer Reviewed / Open Access
• [Journal Article] The CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells. (2019)
  • Author(s): Zhang L, Noguchi YT, Nakayama H, Kaji T, Tsujikawa K, Ikemoto-Uezumi M, Uezumi A, Okada Y, Doi T, Watanabe S, Braun T, Fujio Y, Fukada SI.
  • Journal Title: Cell Rep Volume: 19 Issue: 8 Pages: 2154-63
  • DOI: 10.1016/j.celrep.2019.10.057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice. (2019)
  • Author(s): 1.Imaeda A, Tanaka S, Tonegawa K, Fuchigami S, Obana M, Maeda M, Kihara M, Kiyonari H, Conway SJ, Fujio Y, Nakayama H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 510 Issue: 1 Pages: 149-155
  • DOI: 10.1016/j.bbrc.2019.01.070
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodeling after myocardial infarction (2019)
  • Author(s): Matsumoto, K., Obana, M., Kobayashi, A., Miyagawa, S., Maeda, M., Sakata, Y., Nakayama, H., Sawa, Y., Fujio, Y.
  • Journal Title: Cardiovasc. Res. Volume: 115 Issue: 4 Pages: 765-775
  • DOI: 10.1093/cvr/cvy254
  • Peer Reviewed / Open Access
• [Journal Article] The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation (2018)
  • Author(s): Shirakura Keisuke、Ishiba Ryosuke、Kashio Taito、Funatsu Risa、Tanaka Toru、Fukada So-ichiro、Ishimoto Kenji、Hino Nobumasa、Kondoh Masuo、Ago Yukio、Fujio Yasushi、Yano Kiichiro、Doi Takefumi、Aird William C.、Okada Yoshiaki
  • Journal Title: Journal of Cell Science Volume: 132 Pages: 220228-220228
  • DOI: 10.1242/jcs.220228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caveolae-specific CaMKII signaling in the regulation of voltage-dependent calcium channel and cardiac hypertrophy. (2018)
  • Author(s): Tanaka, S., Fujio, Y., Nakayama, H.
  • Journal Title: Front. Physiol. Volume: 9 Pages: 1081-1081
  • DOI: 10.3389/fphys.2018.01081
  • Peer Reviewed / Open Access
• [Journal Article] Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer. (2018)
  • Author(s): Shintani, T., Higashisaka, K., Maeda, M., Hamada, M., Tsuji, R., Kurihara, K., Kashiwagi, Y., Sato, A., Obana, M., Yamamoto, A., Kawasaki, K., Lin, Y., Kijima, T., Kinehara, Y., Miwa, Y., Maeda, S., Morii, E., Kumanogoh, A., Tsutsumi, Y., Nagatomo, I., Fujio, Y.
  • Journal Title: Oncotarget Volume: 9 Issue: 101 Pages: 37520-37533
  • DOI: 10.18632/oncotarget.26494
  • Peer Reviewed / Open Access
• [Presentation] Adult murine cardiomyocytes exhibit reparative/regenerative activities in the healing process of myocarditis. (2020)
  • Author(s): Fujio, Y., Miyawaki, A., Matsumoto, K., Tanaka, S., Maeda, M., Obana, M.
  • Organizer: 4th Annual 2020 International Hawaii Cardiovascular Symposium
  • Int'l Joint Research / Invited
• [Presentation] 細胞死が惹起する心筋炎症と組織修復：新たな心不全治療を目指して (2020)
  • Author(s): 藤尾 慈、宮脇昭光、尾花理徳、松本浩太朗、前田真貴子
  • Organizer: 日本薬学会第140年会
  • Invited
• [Presentation] 哺乳類心筋細胞の細胞周期活性誘導化合物のスクリーニング系の構築 (2020)
  • Author(s): 松井 理紗、福山 尚希、亀谷 祐介、和田 祐理子、松本 浩太朗、前田 真貴子、尾花 理徳、藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 転写因子OASISの阻害は腎線維化を抑制する (2020)
  • Author(s): 山本彩葉、尾花理徳、中江崇文、三宅芳明、光岡小百合、前田真貴子、今泉和則、松本浩太朗、藤尾慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 心線維芽細胞β2アドレナリン受容体シグナルはパラクラインを介して心臓の肥大を惹起する (2020)
  • Author(s): 今枝 厚貴、田中 翔大、松本 浩太朗、前田 真貴子、尾花 理徳、藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Dad1は細胞接着の障害によって誘導される心筋細胞死を抑制する (2020)
  • Author(s): 森 翔太、木村 瑠美、 渕上 翔太、松本 浩太朗、前田 真貴子、 尾花 理徳、 藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] アドレナリンβ2受容体刺激はｃＡＭＰ/PKA/CREB経路を介したArid5a発現誘導によりIL-6の産生を亢進させる (2020)
  • Author(s): 田中翔大、今枝厚貴、松本浩太朗、前田真貴子、尾花理徳、藤尾慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] CGRRF1の過剰発現は培養心筋細胞の肥大を誘導する (2019)
  • Author(s): 木下真希、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] 成体マウスにおける単核心筋細胞の特性解析 (2019)
  • Author(s): 中安佑介、松井理紗、福山尚希、亀谷祐介、和田祐理子、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] Blockade of NKG2D / NKG2D Ligand Interaction Attenuated Post-Infarct Myocardial Injury. (2018)
  • Author(s): Matsumoto, K., Obana, M., Kobayashi, A.,Kihara, M.,Shioi, G., Miyagawa, S., Maeda, M.,Sakata,Y., Nakayama, H., Sawa, Y.,Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Remarks] 臨床薬効解析学分野
  • URL: http://www.phs.osaka-u.ac.jp/homepage/b014/