Single-cell pathological dynamics in tissue repair and remodeling after myocardial infarction

• Project/Area Number: 19K17587
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ko Toshiyuki 東京大学, 医学部附属病院, 特任助教 (00836059)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 心不全 / 心筋梗塞 / シングルセル解析 / 空間的遺伝子発現解析 / 一細胞解析 / 系譜追跡

Outline of Research at the Start

申請者はこれまで心臓の一細胞RNA-seq解析を行ってきたが、一細胞解析の欠点として、解析した細胞がどのような系譜を辿ってきたのかを検証できないことが挙げられる。
本研究では一細胞レベルでの細胞系譜追跡を可能にするPolyloxマウスを用いて、心筋梗塞後に心筋及び非心筋細胞に生じる経時的遺伝子発現応答変化，細胞間系譜変化を一細胞レベルで同時に解析して明らかにすることを目的としている。本研究は虚血性心不全の新規治療法を創出する基盤になると期待されるだけでなく、本研究で構築される系譜追跡とトランスクリプトーム同時解析による解析方法は、他の疾患モデルや生体組織の解析にも応用可能である。

Outline of Final Research Achievements

This study aimed to perform spatiotemporal transcriptome analysis to understand the pathophysiology of myocardial infarction. To investigate the spatiotemporal regulation of gene expression in the heart after myocardial infarction, we performed single-nucleus RNA-seq and spatial transcriptome analysis on heart tissue on days 1, 7, and 14 after myocardial infarction or sham surgery. These analyses revealed that the expression of mechano-stress-responsive genes were up-regulated specifically in the ischemic border zone during the acute phase of post-infarction period. In addition, we found that Htra3, a gene identified by single-cell RNA-seq analysis of cardiac fibroblasts, plays a cardioprotective role in both pressure overload and ischemia.

Academic Significance and Societal Importance of the Research Achievements

本研究で認められたメカノストレス関連遺伝子やHtra3はいずれも心筋梗塞においては心保護的な役割を果たしており、新規治療ターゲットであると言える。また、本研究で取得したシングルセル・シングル核RNA-seqやSpatial transcriptomeのデータが今後論文として公開されれば、今後他の研究にもpublic dataとして利用されることで、一層この分野の研究進展に資するものであると思われる。

Research Products

• [Journal Article] Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis (2022)
  • Author(s): T. Ko, S. Nomura, K. Fujita, S. Yamada, T. Fujita, M. Satoh, C. Oka, M. Katoh, M. Ito, M. Katagiri, T. Sassa, B. Zhang, S. Hatsuse, T. Yamada, M. Harada, H. Toko, E. Amiya, M. Hatano, O. Kinoshita, K. Nawata, M. Ono, M. Ikeuchi, H. Morita, H. Aburatani, I. Komuro
  • Journal Title: Nature communications Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] 特集 心不全のすべて-増え続ける心不全患者にどう対峙するか トピックス 心不全に対するprecision medicineの展望 (2021)
  • Author(s): 候 聡志
  • Journal Title: 内科 Volume: 128 Issue: 1 Pages: 121-124
  • DOI: 10.15106/j_naika128_121
  • ISSN: 0022-1961, 2432-9452
  • Year and Date: 2021-07-01
• [Journal Article] Single-Cell Analysis Revealed the Role of CD8+ Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure (2021)
  • Author(s): Komai Kyoko、Ito Minako、Nomura Seitaro、Shichino Shigeyuki、Katoh Manami、Yamada Shintaro、Ko Toshiyuki、Iizuka-Koga Mana、Nakatsukasa Hiroko、Yoshimura Akihiko
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 763647-763647
  • DOI: 10.3389/fimmu.2021.763647
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury (2021)
  • Author(s): Hasegawa S, Inoue T, Nakamura Y, Fukaya D, Uni R, Wu CH, Fujii R, Peerapanyasut W, Taguchi A, Kohro T, Yamada S, Katagiri M, Ko T, Nomura S, Nakanishi Ozeki A, Susaki EA, Ueda HR, Akimitsu N, Wada Y, Komuro I, Nangaku M, Inagi R.
  • Journal Title: J Am Soc Nephrol. Volume: - Issue: 7 Pages: 1599-1615
  • DOI: 10.1681/asn.2020121723
  • NAID: 120007174517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] シングルセル解析に基づく循環器病態研究 (2021)
  • Author(s): 候 聡志、山田 臣太郎、野村 征太郎
  • Journal Title: Journal of JCS Cardiologists Volume: 30 Issue: 0 Pages: 43-50
  • DOI: 10.1253/jjcsc.30.0_43
  • NAID: 130008082135
  • ISSN: 0918-9599, 2433-2852
  • Open Access
• [Journal Article] Author Correction: CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor (2021)
  • Author(s): Ishizuka Masato、Harada Mutsuo、Nomura Seitaro、Ko Toshiyuki、et al.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 3426-3426
  • DOI: 10.1038/s41598-021-91788-x
  • Peer Reviewed / Open Access
• [Journal Article] CXCR7 ameliorates myocardial infarction as a β arrestin-biased receptor (2021)
  • Author(s): Ishizuka et al.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 3426-3426
  • DOI: 10.1038/s41598-021-83022-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 特集 循環器疾患バイオマーカー 有用性と可能性 治す12 DNA 損傷評価に基づく拡張型心筋症患者の精密医療 (2020)
  • Author(s): 候 聡志
  • Journal Title: Heart View Volume: 24 Issue: 10 Pages: 994-1000
  • DOI: 10.18885/HV.0000000322
  • ISSN: 1342-6591
  • Year and Date: 2020-10-09
• [Journal Article] Omega-3 fatty acid prevents the development of heart failure by changing fatty acid composition in the heart (2020)
  • Author(s): Toko Haruhiro、Morita Hiroyuki、Katakura Masanori、Hashimoto Michio、Ko Toshiyuki、Bujo Satoshi、Adachi Yusuke、Ueda Kazutaka、Murakami Haruka、Ishizuka Masato、Guo Jiaxi、Zhao Chunxia、Fujiwara Takayuki、Hara Hironori、Takeda Norifumi、Takimoto Eiki、Shido Osamu、Harada Mutsuo、Komuro Issei
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15553-15553
  • DOI: 10.1038/s41598-020-72686-0
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure (2020)
  • Author(s): Yamaguchi Toshihiro、Sumida Tomokazu S.、Nomura Seitaro、Satoh Masahiro、Higo Tomoaki、Ito Masamichi、Ko Toshiyuki、Fujita Kanna、Sweet Mary E.、Sanbe Atsushi、Yoshimi Kenji、Manabe Ichiro、Sasaoka Toshikuni、Taylor Matthew R. G.、Toko Haruhiro、Takimoto Eiki、Naito Atsuhiko T.、Komuro Issei
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4364-4364
  • DOI: 10.1038/s41467-020-18128-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantification of DNA damage in heart tissue as a novel prediction tool for therapeutic prognosis of patients with dilated cardiomyopathy. (2019)
  • Author(s): Ko T, Fujita K, Nomura S, Uemura Y, Yamada S, Tobita T, Katoh M, Satoh M, Ito M, Domoto Y, Hosoya Y, Amiya E, Hatano M, Morita H, Fukayama M, Aburatani H, Komuro I.
  • Journal Title: JACC: Basic to Translational Science Volume: 4(6) Pages: 670-680
  • Peer Reviewed / Open Access
• [Presentation] Aberrant Interaction Between TEAD1 and Lamin A/C Impairs Cardiomyocyte Maturation in LMNA-related Cardiomyopathy (2022)
  • Author(s): Toshiyuki Ko
  • Organizer: 第86回日本循環器学会学術集会 Special Session「Single Cell Analysis in Cardiovascular Disease」
  • Invited
• [Presentation] Cardiac Fibroblasts are Critically Involved in the Development of Heart Failure by Inducing Cardiomyocyte Senescence (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 米国心臓協会（American Heart Association）Scientific Sessions 2021, Melvin L. Marcus Early Career Investigator Award
  • Int'l Joint Research
• [Presentation] Single-cell multiomic analysis of both knock-in mouse and iPSCMs identifies the mechanism of maturation abnormality in heart caused by LMNA Q353R mutation (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 第38回国際心臓研究会日本部会 Young Investigator Award最優秀賞
• [Presentation] Mechanical Stress on Cardiac Fibroblasts Triggers Phenotypic Conversion in Cardiomyocytes Leading to Heart Failure (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 第85回日本循環器学会学術集会 Young Investigator Award
• [Presentation] Single-Cell Analysis to Explore the Molecular Pathology of Heart Failure (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 第85回日本循環器学会学術集会シンポジウム「Molecular mechanisms of heart failure」
  • Invited
• [Presentation] Single-Cell Analysis to Explore the Molecular Pathology of Heart Failure (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 日本循環器学会
  • Invited
• [Presentation] Mechanical Stress on Cardiac Fibroblasts Triggers Phenotypic Conversion in Cardiomyocytes Leading to Heart Failure (2021)
  • Author(s): Toshiyuki Ko
  • Organizer: 日本循環器学会
• [Presentation] Single cell RNA-seq of human cardiomyocytes revealed DNA damage response as a novel predictor for therapeutic prognosis in heart failure patients with dilated cardiomyopathy (2019)
  • Author(s): Toshiyuki Ko
  • Organizer: International Society for Heart Research World Congress 2019
  • Int'l Joint Research
• [Presentation] Quantification of DNA Damage in Heart Tissue as A Novel Prediction Tool for Therapeutic Prognosis (2019)
  • Author(s): Toshiyuki Ko, Seitaro Nomura, Masaru Hatano, Issei Komuro
  • Organizer: 第23回日本心不全学会学術集会
• [Presentation] DNA傷害定量評価に基づく拡張型心筋症患者の治療予後予測 (2019)
  • Author(s): Toshiyuki Ko, Seitaro Nomura, Masaru Hatano, Issei Komuro
  • Organizer: 第67回日本心臓病学会学術集会