Overexpression of Gata4, Mef2c, and Tbx5 Generates Induced Cardiomyocytes Via Direct Reprogramming and Rare Fusion in the Heart

Isomi, Mari; Sadahiro, Taketaro; Yamakawa, Hiroyuki; Fujita, Ryo; Yamada, Yuichi; Abe, Yuto; Murakata, Yoshiko; Akiyama, Tomohiro; Shu, Tsugumine; Mizukami, Hiroaki; Fukuda, Keiichi; Ieda, Masaki

doi:10.1161/circulationaha.120.052799

Cited by 13 publications

(12 citation statements)

References 5 publications

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“…The fact that this is a BAC insert, allows for investigating the spatiotemporal expression of Tbx5 in the adult heart, without inducing a cardiac phenotype 25 . Importantly, our transgene is capable of lineage-tracing mostly ventricular Tbx5-expressing cardiac cells, which may be important for ventricle-specific repair/regeneration, in-line with recent published basic research and preclinical data [66][67][68] . In our study, Tbx5 re-activated CMs were located close to the lesion areas, but a few were also observed in non-injured areas of the adult heart.…”

Section: Discussionsupporting

confidence: 72%

“…The fact that this is a BAC insert, allows for investigating the spatiotemporal expression of Tbx5 in the adult heart, without inducing a cardiac phenotype 23 . Importantly, our transgene is capable of lineage-tracing mostly ventricular Tbx5-expressing cardiac cells, which may be important for ventricle-specific repair/regeneration, in-line with recent published basic research and preclinical data [64][65][66] In humans, TBX5 is expressed in both the embryonic and adult four-chambered heart, in yet unidentified cardiac cell populations 67 . In the adult mouse, Tbx5 has been shown to be primarily expressed in the atria but not in the ventricles, in the absence of injury, which we also observed 43 .…”

Section: Discussionsupporting

confidence: 72%

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Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart

Siatra

Vatsellas

Chatzianastasiou

et al. 2022

Preprint

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The single curative measure for heart failure patients is total heart transplantation, which is limited due to a shortage of donors, the need for immunosuppression and economic costs. Therefore, there is an urgent unmet need for identifying cell populations capable of cardiac regeneration that we will be able to trace and monitor. Injury to the adult mammalian cardiac muscle, often leads to a heart attack through the irreversible loss of a large number of cardiomyocytes, due to an idle regenerative capability. Recent reports in zebrafish indicate that Tbx5a is a vital transcription factor for cardiomyocyte regeneration. Preclinical data underscore the cardioprotective role of Tbx5 upon heart failure. Data from our earlier murine developmental studies have pinpointed a prominent unipotent Tbx5-expressing embryonic cardiac precursor cell population able to form cardiomyocytes, in vivo, in vitro and ex vivo. Using a developmental approach to an adult heart injury model and by employing a lineage-tracing mouse model as well as the use of single-cell RNA-seq technology, we identify a Tbx5-expressing ventricular cardiomyocyte-like precursor population, in the injured adult mammalian heart. The transcriptional profile of that precursor cell population is closer to that of neonatal than embryonic cardiomyocyte precursors. Tbx5, a cardinal cardiac development transcription factor, lies in the centre of a ventricular adult precursor cell population, which seems to be affected by neurohormonal spatiotemporal cues. The identification of a Tbx5-specific cardiomyocyte precursor-like cell population, which is capable of dedifferentiating and potentially deploying a cardiomyocyte regenerative program, provides a clear target cell population for translationally-relevant heart interventional studies.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 72%

Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart

Siatra

Vatsellas

Chatzianastasiou

et al. 2022

Preprint

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“…SeV-GMT appears to be more efficient than the retroviral vector in both mouse and human cardiac reprogramming, suggesting its potential for future heart regenerative studies. Follow-up study also confirms that SeV-MGT induces iCMs in MI mouse model with lineage tracing [ 67 ] and SeV-GMT treatment significantly improves fractional shortening (FS) compared to pMX-MGT after 4 weeks which indicates its superior cardiac protection effect.…”

Section: Clinical Translational Progress For Cardiac Reprogrammingmentioning

confidence: 67%

Improving Cardiac Reprogramming for Heart Regeneration in Translational Medicine

Liu

Guo

et al. 2021

Cells

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Direct reprogramming of fibroblasts into CM-like cells has emerged as an attractive strategy to generate induced CMs (iCMs) in heart regeneration. However, low conversion rate, poor purity, and the lack of precise conversion of iCMs are still present as significant challenges. In this review, we summarize the recent development in understanding the molecular mechanisms of cardiac reprogramming with various strategies to achieve more efficient iCMs. reprogramming. Specifically, we focus on the identified critical roles of transcriptional regulation, epigenetic modification, signaling pathways from the cellular microenvironment, and cell cycling regulation in cardiac reprogramming. We also discuss the progress in delivery system optimization and cardiac reprogramming in human cells related to preclinical applications. We anticipate that this will translate cardiac reprogramming-based heart therapy into clinical applications. In addition to optimizing the cardiogenesis related transcriptional regulation and signaling pathways, an important strategy is to modulate the pathological microenvironment associated with heart injury, including inflammation, pro-fibrotic signaling pathways, and the mechanical properties of the damaged myocardium. We are optimistic that cardiac reprogramming will provide a powerful therapy in heart regenerative medicine.

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“…While AdV and LeV induced equivalent expression levels of GMT factors and had a similar transdifferentiation capacity compared to ReV polycistronic vectors [147], SeV polycistronic GMT vectors injected into mouse hearts after MI, achieved a greater efficiency of DCR with respect to ReVs [148] 1 week after injection, with a relative improvement in cardiac function and a reduction in fibrosis [148]. SeV-GMT generates iCMs through largely bona fide cardiac reprogramming and not through fusion events between cardiomyocytes and CFs [149]. Moreover, the beneficial effects of in vivo SeV-GMT reprogramming can be appreciated up to 12 weeks after MI in immunocompetent mice [149].…”

Section: Targeting Cardiac Fibroblasts For In Vivo Direct Cardiac Reprogrammingmentioning

confidence: 99%

“…SeV-GMT generates iCMs through largely bona fide cardiac reprogramming and not through fusion events between cardiomyocytes and CFs [149]. Moreover, the beneficial effects of in vivo SeV-GMT reprogramming can be appreciated up to 12 weeks after MI in immunocompetent mice [149].…”

Section: Targeting Cardiac Fibroblasts For In Vivo Direct Cardiac Reprogrammingmentioning

confidence: 99%

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

Testa

Benedetto

Passaro

2021

IJMS

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The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

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Overexpression of Gata4, Mef2c, and Tbx5 Generates Induced Cardiomyocytes Via Direct Reprogramming and Rare Fusion in the Heart

Cited by 13 publications

References 5 publications

Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart

Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart

Improving Cardiac Reprogramming for Heart Regeneration in Translational Medicine

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

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