貞廣　威太郎 (サダヒロ　タケタロウ)

Sadahiro, Taketaro

写真a

所属（所属キャンパス）

医学部 内科学教室（循環器） （信濃町）

職名

助教（有期）
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  • ライフサイエンス / 循環器内科学

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  • 循環器画像検査

  • 心筋再生

  • 心臓リハビリテーション

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  • Cardiac reprogramming reduces inflammatory macrophages and improves cardiac function in chronic myocardial infarction

    Abe Y., Tani H., Sadahiro T., Yamada Y., Akiyama T., Nakano K., Honda S., Ko S., Anzai A., Ieda M.

    Biochemical and Biophysical Research Communications 690 2024年01月

    ISSN  0006291X

    　概要を見る

    Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.

  • Flk1 Deficiency and Hypoxia Synergistically Promote Endothelial Dysfunction, Vascular Remodeling, and Pulmonary Hypertension

    Akiyama T., Sadahiro T., Yamada Y., Fujita R., Abe Y., Nakano K., Honda S., Ema M., Kubota Y., Sakai S., Hizawa N., Ieda M.

    Arteriosclerosis, Thrombosis, and Vascular Biology 43 （ 9 ） 1668 - 1683 2023年09月

    ISSN  10795642

    　概要を見る

    BACKGROUND: The mechanisms underlying pulmonary hypertension (PH) remain largely unknown; further, why advanced vascular remodeling preferentially occurs in arterioles is yet to be answered. VEGF (vascular endothelial growth factor) regulates angiogenesis through Flk1 (fetal liver kinase 1) and Flt1 (fms-like tyrosine kinase 1) on endothelial cells (ECs), which may be related to PH pathogenesis. However, spatiotemporal expression patterns of Flk1 and Flt1 in the pulmonary vascular system and the role of endothelial Flk1 in PH development remain poorly understood. METHODS: We analyzed multiple reporter mice, including Flk1-GFP (green fluorescent protein) bacterial artificial chromosome transgenic (Tg), Flt1-DsRed bacterial artificial chromosome Tg, and Flk1-GFP/Flt1-DsRed double Tg mice, to determine the spatiotemporal expression of Flk1 and Flt1 in hypoxia-induced PH. We also used Cdh5CreERT2/Flk1f/f/Tomato (Flk1-KO [knockout]) mice to induce EC-specific Flk1 deletion and lineage tracing in chronic hypoxia. RESULTS: Flk1 was specifically expressed in the ECs of small pulmonary vessels, including arterioles. Conversely, Flt1 was more broadly expressed in the ECs of large- to small-sized vessels in adult mouse lungs. Intriguingly, Flk1+ECs were transiently increased in hypoxia with proliferation, whereas Flt1 expression was unchanged. Flk1-KO mice did not exhibit pulmonary vascular remodeling nor PH in normoxia; however, the arteriolar ECs changed to a cuboidal shape with protrusion. In hypoxia, Flk1 deletion exacerbated EC dysfunction and reduced their number via apoptosis. Additionally, Flk1 deletion promoted medial thickening and neointimal formation in arterioles and worsened PH. Mechanistically, lineage tracing revealed that neointimal cells were derived from Flk1-KO ECs. Moreover, RNA sequencing in pulmonary ECs demonstrated that Flk1 deletion and hypoxia synergistically activated multiple pathways, including cell cycle, senescence/apoptosis, and cytokine/growth factor, concomitant with suppression of cell adhesion and angiogenesis, to promote vascular remodeling. CONCLUSIONS: Flk1 and Flt1 were differentially expressed in pulmonary ECs. Flk1 deficiency and hypoxia jointly dysregulated arteriolar ECs to promote vascular remodeling. Thus, dysfunction of Flk1+ECs may contribute to the pathogenesis of advanced vascular remodeling in pulmonary arterioles.

  • MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes

    Kojima H., Sadahiro T., Muraoka N., Yamakawa H., Hashimoto H., Ishii R., Gosho M., Abe Y., Yamada Y., Nakano K., Honda S., Fujita R., Akiyama T., Sunagawa Y., Morimoto T., Tsukahara T., Hirai H., Fukuda K., Ieda M.

    Stem Cell Reports 18 （ 6 ） 1274 - 1283 2023年06月

    ISSN  22136711

    　概要を見る

    Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.

  • Generation of a MyoD knock-in reporter mouse line to study muscle stem cell dynamics and heterogeneity

    Fujita R., Mizuno S., Sadahiro T., Hayashi T., Sugasawa T., Sugiyama F., Ono Y., Takahashi S., Ieda M.

    iScience 26 （ 5 ）  2023年05月

    　概要を見る

    Myoblast determination protein 1 (MyoD) dynamics define the activation status of muscle stem cells (MuSCs), aiding in muscle tissue regeneration after injury. However, the lack of experimental platforms to monitor MyoD dynamics in vitro and in vivo has hampered the investigation of fate determination and heterogeneity of MuSCs. Herein, we report a MyoD knock-in (MyoD-KI) reporter mouse expressing tdTomato at the endogenous MyoD locus. Expression of tdTomato in MyoD-KI mice recapitulated the endogenous MyoD expression dynamics in vitro and during the early phase of regeneration in vivo. Additionally, we showed that tdTomato fluorescence intensity defines MuSC activation status without immunostaining. Based on these features, we developed a high-throughput screening system to assess the effects of drugs on the behavior of MuSCs in vitro. Thus, MyoD-KI mice are an invaluable resource for studying the dynamics of MuSCs, including their fate decisions and heterogeneity, and for drug screening in stem cell therapy.

  • Development of direct cardiac reprogramming for clinical applications

    Yamada Y., Sadahiro T., Ieda M.

    Journal of Molecular and Cellular Cardiology 178   1 - 8 2023年05月

    ISSN  00222828

    　概要を見る

    The incidence of cardiovascular diseases is increasing worldwide, and cardiac regenerative therapy has great potential as a new treatment strategy, especially for ischemic heart disease. Direct cardiac reprogramming is a promising new cardiac regenerative therapy that uses defined factors to induce transdifferentiation of endogenous cardiac fibroblasts (CFs) into induced cardiomyocyte-like cells (iCMs). In vivo reprogramming is expected to restore lost cardiac function without necessitating cardiac transplantation by converting endogenous CFs that exist abundantly in cardiac tissues directly into iCMs. Indeed, we and other groups have demonstrated that in vivo cardiac reprogramming improves cardiac contractile function and reduces scar area after acute myocardial infarction (MI). Recently, we demonstrated that in vivo cardiac reprogramming is an innovative cardiac regenerative therapy that not only regenerates the myocardium, but also reverses fibrosis by inducing the quiescence of pro-fibrotic fibroblasts, thereby improving heart failure in chronic MI. In this review, we summarize the recent progresses in in vivo cardiac reprogramming, and discuss its prospects for future clinical applications and the challenges of direct human reprogramming, which has been a longstanding issue.

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