• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Comprehensive Platform for Studying Molecular Mechanisms Regulating Cardiomyocyte Maturation

Research Project

Project/Area Number 19KK0219
Research Category

Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionJichi Medical University

Principal Investigator

魚崎 英毅  自治医科大学, 医学部, 准教授 (90740803)

Co-Investigator(Kenkyū-buntansha) 関 満  自治医科大学, 医学部, 講師 (20822357)
升本 英利  国立研究開発法人理化学研究所, 生命機能科学研究センター, 上級研究員 (70645754)
Project Period (FY) 2019-10-07 – 2023-03-31
Project Status Granted (Fiscal Year 2020)
Budget Amount *help
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2022: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords心筋細胞 / 成熟 / 比較トランスクリプトーム / 心臓 / 発生・発達 / 多能性幹細胞
Outline of Research at the Start

多能性幹細胞から得られる心筋細胞(PSC-CMs)は再生医療に加えて、疾患研究や創薬への利用が期待されている。しかし、PSC-CMsは、成体の心筋細胞とはその特性に大きな乖離がある。今後の応用を進めるためには、ヒト心筋細胞の成熟過程の理解と、その理解に基づいた成熟法や解析基盤が必要となる。Johns Hopkins大学Chulan Kwon准教授は新生仔ラットの心臓へPSC-CMsを移植することで、成熟した成体型のPSC-CMsを得る生体内成熟法を確立した。本研究では、生体内成熟法を用いることで、成熟過程のトランスクリプトームと、成熟レポーター細胞の開発と検証を行う。

Outline of Annual Research Achievements

本年度は新型コロナウイルス感染症のため、共同研究先であるJohns Hopkins大学へ渡航しての実験を行うことができなかったため、全体的な研究計画を見直し、アプローチを変えて研究を進めた。
(1) Johns Hopkins大学では、研究代表者の魚崎が研究の端緒を掴んだ心筋細胞成熟過程におけるPGC1a/bの機能解析を行い、PGC1a/bがYAPおよびSF3B2を介して、心筋細胞の成熟を制御していることを明らかにし、論文発表を行った(Murphy, Nature Communication, 2021)。
(2) 自治医科大学ではマウスおよびヒトにおいて成熟マーカー遺伝子の解析を行った。2019年度に樹立したマウスノックインES細胞からキメラマウスを作出し、交配を行ったが、いずれの株も生殖系列に寄与せず、マーカー遺伝子を有する産仔を得ることができなかった。現在、AAVを用いた受精卵でノックインを行うための準備を進めている。一方ヒトiPS細胞において4系統のノックイン細胞を樹立し、うち3系統で成熟が進むと蛍光タンパクを発現し、レポーターとして有用であることが確認できた。
(3) 試験管内でPSC-CMsのサルコメア機能評価を容易にするための手法開発を行い、論文発表を行った(Ahmed, J Vis Exp, 2021)。
(4) 哺乳類と比べて非常に未熟な段階で出産するオポッサムとマウスの比較トランスクリプトームを行い、心筋細胞の増殖・成熟制御の新しいメカニズムを同定し、現在論文を投稿中である(理化学研究所木村博士との共同研究)。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

概要に記載したとおり、新型コロナウイルス感染症の広がりより、渡米しての実験が行えていない。代替アプローチにより、研究を進めている。
マウスノックインES細胞により作出したキメラマウスからレポーターを持つ産仔が得られず、新しいアプローチでノックインマウスの樹立をMax Planck Florida Instituteの西園博士と進めていたが、西園博士が2021年4月に金沢医大に着任するため帰国したため、実験中断を余儀なくされた。2021年度に国内で継続予定である。

Strategy for Future Research Activity

少なくとも渡米再開には新型コロナウイルスに対するワクチン接種が日米両国で進み、感染症がコントロール可能になる必要があるが、早くとも2021年度前期では期待できない。状況が改善すれば渡米し、必要な実験を進めたい。
すでにヒトiPS細胞で成熟を反映できる新しいレポーターの候補が得られているため、成熟レポーター陽性細胞の機能評価等を進め、また、細胞に対する機械的刺激の影響を評価する実験を先行して進める。

Report

(2 results)
  • 2020 Research-status Report
  • 2019 Research-status Report

Research Products

(41 results)

All 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (15 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 15 results,  Open Access: 11 results) Presentation (20 results) (of which Int'l Joint Research: 8 results,  Invited: 13 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] Johns Hopkins大学/Max Planck Florida Institute(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Johns Hopkins University(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Max Planck Florida Institute(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B22021

    • Author(s)
      Murphy Sean A.、Miyamoto Matthew、Kervadec Anais、Kannan Suraj、Tampakakis Emmanouil、Kambhampati Sandeep、Lin Brian Leei、Paek Sam、Andersen Peter、Lee Dong-Ik、Zhu Renjun、An Steven S.、Kass David A.、Uosaki Hideki、Colas Alexandre R.、Kwon Chulan
    • Journal Title

      Nature Communications

      Volume: 12

    • DOI

      10.1038/s41467-021-21957-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-viral ex vivo genome-editing in mouse bona fide hematopoietic stem cells with CRISPR/Cas9.2021

    • Author(s)
      Byambaa S, Uosaki H, Ohmori T, Hara H, Endo H, Nureki O, Hanazono Y.
    • Journal Title

      Molecular Therapy - Methods & Clinical Development

      Volume: 20 Pages: 451-462

    • DOI

      10.1016/j.omtm.2021.01.001

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sarcomere Shortening of Pluripotent Stem Cell-Derived Cardiomyocytes using Fluorescent-Tagged Sarcomere Proteins.2021

    • Author(s)
      Ahmed Razan E.、Chanthra Nawin、Anzai Tatsuya、Koiwai Keiichiro、Murakami Tomoki、Suzuki Hiroaki、Hanazono Yutaka、Uosaki Hideki
    • Journal Title

      Journal of Visualized Experiments

      Volume: 169

    • DOI

      10.3791/62129

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fetal sheep support the development of hematopoietic cells in vivo from human induced pluripotent stem cells2021

    • Author(s)
      Abe Tomoyuki、Uosaki Hideki、Shibata Hiroaki、Hara Hiromasa、Sarentonglaga Borjigin、Nagao Yoshikazu、Hanazono Yutaka
    • Journal Title

      Experimental Hematology

      Volume: 95 Pages: 46-57

    • DOI

      10.1016/j.exphem.2020.12.006

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Novel Fluorescent Reporter System Identifies Laminin-511/521 as Potent Regulators of Cardiomyocyte Maturation2021

    • Author(s)
      Chanthra Nawin、Abe Tomoyuki、Miyamoto Matthew、Sekiguchi Kiyotoshi、Kwon Chulan、Hanazono Yutaka、Uosaki Hideki
    • Journal Title

      Scientific Reports

      Volume: 10 Pages: 4249-4249

    • DOI

      10.1038/s41598-020-61163-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel device prototyping for endoscopic cell sheet transplantation using a three-dimensional printed simulator2020

    • Author(s)
      Osada Hiroaki、Ho Wen-Jin、Yamashita Hideki、Yamazaki Kazuhiro、Ikeda Tadashi、Minatoya Kenji、Masumoto Hidetoshi
    • Journal Title

      Regenerative Therapy

      Volume: 15 Pages: 258-264

    • DOI

      10.1016/j.reth.2020.10.007

    • NAID

      120006898124

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of a heart-on-a-chip microdevice based on human iPS cells for the evaluation of human heart tissue function2020

    • Author(s)
      Abulaiti Mosha、Yalikun Yaxiaer、Murata Kozue、Sato Asako、Sami Mustafa M.、Sasaki Yuko、Fujiwara Yasue、Minatoya Kenji、Shiba Yuji、Tanaka Yo、Masumoto Hidetoshi
    • Journal Title

      Journal of Cardiac Surgery

      Volume: 10 Pages: 19201-19201

    • DOI

      10.1038/s41598-020-76062-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Strategies for immune regulation in iPS cell-based cardiac regenerative medicine2020

    • Author(s)
      Murata Kozue、Ikegawa Masaya、Minatoya Kenji、Masumoto Hidetoshi
    • Journal Title

      Inflammation and Regeneration 36

      Volume: 40 Pages: 36-36

    • DOI

      10.1186/s41232-020-00145-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Accuracy of spiked cell counting methods for designing a pre-clinical tumorigenicity study model2020

    • Author(s)
      Osada H, Kawatou M, Takeda M, Jo JI, Murakami T, Tabata Y, Minatoya K, Yamashita JK, Masumoto H.
    • Journal Title

      General Thoracic and Cardiovascular Surgery

      Volume: 6 Pages: 311-318

    • DOI

      10.1016/j.heliyon.2020.e04423

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Rabbit Venous Interposition Model Mimicking Revascularization Surgery using Vein Grafts to Assess Intimal Hyperplasia under Arterial Blood Pressure2020

    • Author(s)
      Nishio Hiroomi、Minatoya Kenji、Masumoto Hidetoshi
    • Journal Title

      Journal of Visualized Experiments

      Volume: 159

    • DOI

      10.3791/60931

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Preparation of Mesh-Shaped Engineered Cardiac Tissues Derived from Human iPS Cells for In Vivo Myocardial Repair2020

    • Author(s)
      Nakane Takeichiro、Abulaiti Mosha、Sasaki Yuko、Kowalski William J.、Keller Bradley B.、Masumoto Hidetoshi
    • Journal Title

      Regenerative Therapy

      Volume: 160 Pages: 258-264

    • DOI

      10.3791/61246

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Generation of novel <i>Il2rg</i>-knockout mice with clustered regularly interspaced short palindromic repeats (CRISPR) and Cas92020

    • Author(s)
      BYAMBAA Suvd、UOSAKI Hideki、HARA Hiromasa、NAGAO Yasumitsu、ABE Tomoyuki、SHIBATA Hiroaki、NUREKI Osamu、OHMORI Tsukasa、HANAZONO Yutaka
    • Journal Title

      Exp. Anim.

      Volume: - Issue: 2 Pages: 189-198

    • DOI

      10.1538/expanim.19-0120

    • NAID

      130007835079

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Brief Review of Current Maturation Methods for Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes2020

    • Author(s)
      Ahmed Razan Elfadil、Anzai Tatsuya、Chanthra Nawin、Uosaki Hideki
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 8

    • DOI

      10.3389/fcell.2020.00178

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Use of Freeze-thawed Embryos for High-efficiency Production of Genetically Modified Mice2020

    • Author(s)
      Nishizono Hirofumi、Darwish Mohamed、Uosaki Hideki、Masuyama Nanami、Seki Motoaki、Abe Hiroyuki、Yachie Nozomu、Yasuda Ryohei
    • Journal Title

      Journal of Visualized Experiments

      Volume: - Pages: 1-1

    • DOI

      10.3791/60808

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Comparative Transcriptome Landscape of Mouse and Human Hearts2020

    • Author(s)
      Tatsuya Anzai, Takanori Yamagata, Hideki Uosaki
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 8

    • DOI

      10.3389/fcell.2020.00268

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] iPS細胞由来心筋細胞を用いた疾患研究の基盤構築2021

    • Author(s)
      魚崎 英毅
    • Organizer
      CVMW2020 心血管代謝週間
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 疾患iPS細胞を用いた病態解明に向けた基盤構築2021

    • Author(s)
      魚崎 英毅
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 蛍光標識サルコメアを利用したiPS細胞由来心筋細胞のサルコメアショートニング2021

    • Author(s)
      魚崎英毅, 安済達也, Nawin Chanthra, Razan E Ahmed, 花園 豊
    • Organizer
      第20回再生医療学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Disease Modeling of Cardiomyopathy Using Pluripotent Stem Cells.2021

    • Author(s)
      Hideki Uosaki
    • Organizer
      MIS-KOREA
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] iPS細胞を用いた心筋症モデリング2021

    • Author(s)
      魚崎英毅
    • Organizer
      第 10 回 Cardiovasucular Thrombosis Seminar
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Research for Cardiac Regenerative Medicine and Heart Diseases Using Pigs as a Large Mammal.2021

    • Author(s)
      Masumoto H.
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Identifying Cross-Organ Similarities During Development and Maturation Arrest of Pluripotent Stem Cell Differentiation2020

    • Author(s)
      Sandeep Kambhampati, Sean Murphy, Hideki Uosaki, Chulan Kwon
    • Organizer
      BMES 2020 Virtual Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] In vitro maturation of cardiomyocytes derived from stem cells.2020

    • Author(s)
      Hideki Uosaki
    • Organizer
      MIS-KOREA
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Heart Failure Treatment Using Engineered 3D Cardiac Sheets.2020

    • Author(s)
      Masumoto H.
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ヒトiPS細胞由来心血管系細胞多層体を用いた新たな重症心不全治療法2020

    • Author(s)
      升本 英利
    • Organizer
      第19回日本再生医療学会総会(共催学術セミナー2)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ヒトiPS細胞由来心血管系細胞多層体を用いた心不全治療法の開発2020

    • Author(s)
      升本 英利
    • Organizer
      第24回日本心不全学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Cardiovascular Regenerative Medicine Supported By Biomaterials And Drug Delivery System.2020

    • Author(s)
      Masumoto H.
    • Organizer
      Controlled Release Society Virtual Annual Meeting 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Hideki Uosaki, Nawin Chanthra, Yutaka Hanazono2020

    • Author(s)
      Hideki Uosaki, Nawin Chanthra, Yutaka Hanazono
    • Organizer
      第8回IRG Meeting
    • Related Report
      2019 Research-status Report
  • [Presentation] In vitro maturation of cardiomyocytes derived from stem cells.2020

    • Author(s)
      Hideki Uosaki
    • Organizer
      MIS-Korea 2020
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] PHENOTYPICAL CORRECTION OF X-SCID MICE AFTER CRISPR/CAS9-MEDIATED UNIVERSAL GENOME-EDITING THERAPY OF HEMATOPOIETIC STEM CELLS2019

    • Author(s)
      Suvd Byambaa, Hideki Uosaki, Hiromasa Hara, Hiroaki Shibata, Tomoyuki Abe,Yasumitsu Nagao, Osamu Nureki, Tsukasa Ohmori, Yutaka Hanazono
    • Organizer
      Frontiers in Genome Engineering 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] ESTABLISHMENT OF SIMULTANEOUS TRIPLE REPORTER SYSTEM FOR HDR/NHEJ/DSB2019

    • Author(s)
      Hiromasa Hara, Hideki Uosaki, Tomoyuki Abe, Hiroaki Shibata, Osamu Nureki, Yutaka Hanazono
    • Organizer
      Frontiers in Genome Engineering 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] FEASIBILITY STUDY OF HOMOLOGOUS RECOMBINATION-BASED GENOME-EDITING THERAPY IN A SWINE MODEL OF X-SCID2019

    • Author(s)
      Yutaka Hanazono, Hiromasa Hara, Hideki Uosaki, Osamu Nureki
    • Organizer
      Frontiers in Genome Engineering 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 相同組換え修復を利用したHPRT1遺伝子のノックイン効率向上2019

    • Author(s)
      樋口真希、小澤高嶺、河野宏光、魚崎英毅、花園豊、太田邦史
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Transcriptional Network Regulating Cardiomyocyte Maturation2019

    • Author(s)
      Hideki Uosaki
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Visualizations of Cardiomyocyte Maturation on Extracellular Matrices Using a Novel Myom2-RFP Reporter Line2019

    • Author(s)
      Nawin Chanthra, Yutaka Hanazono, Hideki Uosaki
    • Organizer
      CVMW 2019
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 心筋細胞の成熟方法、心筋細胞の成熟度評価方法(以下省略)2020

    • Inventor(s)
      魚崎英毅
    • Industrial Property Rights Holder
      魚崎英毅
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 細胞外マトリックス、成熟心筋細胞製造方法、創薬支援方法、治療方法、成熟心筋細胞、及び心筋細胞成熟キット2020

    • Inventor(s)
      魚崎英毅、関口清俊
    • Industrial Property Rights Holder
      自治医科大学、大阪大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-017809
    • Filing Date
      2020
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 心筋細胞の成熟方法、心筋細胞の成熟度評価方法、成熟心筋細胞の純化方法、創薬支援方法、心疾患の治療方法、成熟心筋細胞マーカー、レポーター細胞、成熟心筋細胞、心筋細胞成熟度評価装置 (以下省略)2019

    • Inventor(s)
      魚崎 英毅
    • Industrial Property Rights Holder
      自治医科大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-218998
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-10-10   Modified: 2021-12-27  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi