Tani, Hidenori

写真a

Affiliation

School of Medicine, Joint Research Laboratory for Medical Innovation in Heart Disease （Shinanomachi）

Position

Project Assistant Professor (Non-tenured)/Project Research Associate (Non-tenured)/Project Instructor (Non-tenured)
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Papers 【 Display / hide 】

  • Seamless and non-destructive monitoring of extracellular microRNAs during cardiac differentiation from human pluripotent stem cells

    Sekine O., Kanaami S., Masumoto K., Aihara Y., Morita-Umei Y., Tani H., Soma Y., Umei T.C., Haga K., Moriwaki T., Kawai Y., Ohno M., Kishino Y., Kanazawa H., Fukuda K., Ieda M., Tohyama S.

    Stem Cell Reports （Stem Cell Reports)  18 （ 10 ） 1925 - 1939 2023.10

    ISSN  22136711

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    Monitoring cardiac differentiation and maturation from human pluripotent stem cells (hPSCs) and detecting residual undifferentiated hPSCs are indispensable for the development of cardiac regenerative therapy. MicroRNA (miRNA) is secreted from cells into the extracellular space, and its role as a biomarker is attracting attention. Here, we performed an miRNA array analysis of supernatants during the process of cardiac differentiation and maturation from hPSCs. We demonstrated that the quantification of extracellular miR-489-3p and miR-1/133a-3p levels enabled the monitoring of mesoderm and cardiac differentiation, respectively, even in clinical-grade mass culture systems. Moreover, extracellular let-7c-5p levels showed the greatest increase with cardiac maturation during long-term culture. We also verified that residual undifferentiated hPSCs in hPSC-derived cardiomyocytes (hPSC-CMs) were detectable by measuring miR-302b-3p expression, with a detection sensitivity of 0.01%. Collectively, we demonstrate that our method of seamlessly monitoring specific miRNAs secreted into the supernatant is non-destructive and effective for the quality evaluation of hPSC-CMs.

  • Heart-derived collagen promotes maturation of engineered heart tissue

    Tani H, Kobayashi E, Yagi S, Tanaka K, Kameda-Haga K, Shibata S, Moritoki N, Takatsuna K, Moriwaki T, Sekine O, Umei T.C, Morita Y, Soma Y, Kishino Y, Kanazawa H, Fujita J, Hattori S, Fukuda K, Tohyama S

    Biomaterials （Biomaterials)  299   122174 2023.08

    ISSN  01429612

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    Although the extracellular matrix (ECM) plays essential roles in heart tissue engineering, the optimal ECM components for heart tissue organization have not previously been elucidated. Here, we focused on the main ECM component, fibrillar collagen, and analyzed the effects of collagens on heart tissue engineering, by comparing the use of porcine heart-derived collagen and other organ-derived collagens in generating engineered heart tissue (EHT). We demonstrate that heart-derived collagen induces better contraction and relaxation of human induced pluripotent stem cell-derived EHT (hiPSC-EHT) and that hiPSC-EHT with heart-derived collagen exhibit more mature profiles than those with collagens from other organs. Further, we found that collagen fibril formation and gel stiffness influence the contraction, relaxation, and maturation of hiPSC-EHT, suggesting the importance of collagen types III and type V, which are relatively abundant in the heart. Thus, we demonstrate the effectiveness of organ-specific collagens in tissue engineering and drug discovery.

  • Response by Sadahiro et al to Letter Regarding Article, "Direct Reprogramming Improves Cardiac Function and Reverses Fibrosis in Chronic Myocardial Infarction".

    Sadahiro T, Tani H, Ieda M

    Circulation 148 （ 2 ） 172 - 173 2023.07

    ISSN  0009-7322

  • Cardiac Regenerative Therapy Using Human Pluripotent Stem Cells for Heart Failure: A State-of-the-Art Review

    Y Kishino, S Tohyama, Y Morita, Y Soma, H Tani, M Okada, H Kanazawa, ...

    Journal of Cardiac Failure 29 (4), 503-513 （Journal of Cardiac Failure)  29 （ 4 ） 503 - 513 2023.04

    ISSN  10719164

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    Heart transplantation (HT) is the only definitive treatment available for patients with end-stage heart failure who are refractory to medical and device therapies. However, HT as a therapeutic option, is limited by a significant shortage of donors. To overcome this shortage, regenerative medicine using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and human-induced pluripotent stem cells (hiPSCs), has been considered an alternative to HT. Several issues, including the methods of large-scale culture and production of hPSCs and cardiomyocytes, the prevention of tumorigenesis secondary to contamination of undifferentiated stem cells and non-cardiomyocytes, and the establishment of an effective transplantation strategy in large-animal models, need to be addressed to fulfill this unmet need. Although post-transplantation arrhythmia and immune rejection remain problems, the ongoing rapid technological advances in hPSC research have been directed toward the clinical application of this technology. Cell therapy using hPSC-derived cardiomyocytes is expected to serve as an integral component of realistic medicine in the near future and is being potentially viewed as a treatment that would revolutionize the management of patients with severe heart failure.

  • Direct reprogramming improves cardiac function and reverses fibrosis in chronic myocardial infarction

    H Tani, T Sadahiro, Y Yamada, M Isomi, H Yamakawa, R Fujita, Y Abe, ...

    Circulation 147 (3), 223-238 （Circulation)  147 （ 3 ） 223 - 238 2023.01

    ISSN  00097322

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    Background: Because adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts (CFs) synthesize extracellular matrix after myocardial infarction (MI) to form fibrosis, leading to cardiac dysfunction and heart failure. Therapies that can regenerate the myocardium and reverse fibrosis in chronic MI are lacking. The overexpression of cardiac transcription factors, including Mef2c/Gata4/Tbx5/Hand2 (MGTH), can directly reprogram CFs into induced cardiomyocytes (iCMs) and improve cardiac function under acute MI. However, the ability of in vivo cardiac reprogramming to repair chronic MI with established scars is undetermined. Methods: We generated a novel Tcf21iCre/reporter/MGTH2A transgenic mouse system in which tamoxifen treatment could induce both MGTH and reporter expression in the resident CFs for cardiac reprogramming and fibroblast lineage tracing. We first tested the efficacy of this transgenic system in vitro and in vivo for acute MI. Next, we analyzed in vivo cardiac reprogramming and fusion events under chronic MI using Tcf21iCre/Tomato/MGTH2A and Tcf21iCre/mTmG/MGTH2A mice, respectively. Microarray and single-cell RNA sequencing were performed to determine the mechanism of cardiac repair by in vivo reprogramming. Results: We confirmed the efficacy of transgenic in vitro and in vivo cardiac reprogramming for acute MI. In chronic MI, in vivo cardiac reprogramming converted ≈2% of resident CFs into iCMs, in which a majority of iCMs were generated by means of bona fide cardiac reprogramming rather than by fusion with cardiomyocytes. Cardiac reprogramming significantly improved myocardial contraction and reduced fibrosis in chronic MI. Microarray analyses revealed that the overexpression of MGTH activated cardiac program and concomitantly suppressed fibroblast and inflammatory signatures in chronic MI. Single-cell RNA sequencing demonstrated that resident CFs consisted of 7 subclusters, in which the profibrotic CF population increased under chronic MI. Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by means of conversion of profibrotic CFs to a quiescent antifibrotic state. MGTH overexpression induced antifibrotic effects partly by suppression of Meox1, a central regulator of fibroblast activation. Conclusions: These results demonstrate that cardiac reprogramming could repair chronic MI by means of myocardial regeneration and reduction of fibrosis. These findings present opportunities for the development of new therapies for chronic MI and heart failure.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Elucidation of novel pathophysiology and development of treatment for heart failure using human iPS cell-derived 3D heart tissue

    2023.04
    -
    2026.03

    Grants-in-Aid for Scientific Research, 谷 英典, Grant-in-Aid for Early-Career Scientists, No Setting

    　View Summary

    HFpEFの病態は、高血圧や糖尿病、脂質異常症といった併存症により、全身性に酸化ストレスや炎症が惹起された結果、血管内皮の障害が起き、eNOS が関与するシグナル伝達経路 (eNOS-NO-cGMP-PKG 経路) が障害され、左室の拡張障害が生じることであるというのが近年の動物実験で明らかになってきた。ヒトの細胞、組織においてはHFpEFのモデルは確立しておらず、機序の解明や治療薬の開発も急務となっている。本研究の概要は、「HFpEFにおける心筋拡張障害はヒト心筋組織のどういった変化によって引き起こされるのか」であり、心臓病領域の研究における重要な研究課題を担っている。

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