Ameliorating the Fibrotic Remodeling of the Heart through Direct Cardiac Reprogramming

Bektik, Emre; Fu, Ji-Dong

doi:10.3390/cells8070679

Cited by 24 publications

(18 citation statements)

References 112 publications

(161 reference statements)

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“…Recently, efforts have been addressed at reducing the extent of cardiac fibrotic scar, as it reduces the contractile heart functionality (Talman and Ruskoaho, 2016). Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) represents a new emerging strategy to convert cardiac fibrotic tissue into functional tissue (Bektik and Fu, 2019). Ieda et al (2010) were the first to report direct reprogramming of mouse fibroblasts into beating iCMs through a simultaneous overexpression of GATA binding protein 4 (GATA4), Myocyte enhancer factor 2C (MEF2C), T-box 5 (TBX5) cardiac transcription factors (TFs) both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype

Paoletti

Divieto

Tarricone

et al. 2020

Front. Bioeng. Biotechnol.

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Modulation of microRNA expression holds the promise to achieve direct reprogramming of fibroblasts into cardiomyocyte-like cells as a new strategy for myocardial regeneration after ischemic heart disease. Previous reports have shown that murine fibroblasts can be directly reprogrammed into induced cardiomyocytes (iCMs) by transient transfection with four microRNA mimics (miR-1, 133, 208, and 499, termed "miRcombo"). Hence, study on the effect of miRcombo transfection on adult human cardiac fibroblasts (AHCFs) deserves attention in the perspective of a future clinical translation of the approach. In this brief report, we studied for the first time whether miRcombo transient transfection of AHCFs by non-viral vectors might trigger direct reprogramming of AHCFs into cardiomyocyte-like cells. Initially, efficient miRNA delivery to cells was demonstrated through the use of a commercially available transfection agent (DharmaFECT1). Transient transfection of AHCFs with miRcombo was found to upregulate early cardiac transcription factors after 7 days post-transfection and cardiomyocyte specific marker cTnT after 15 days post-transfection, and to downregulate the expression of fibroblast markers at 15 days post-transfection. The percentage of cTnT-positive cells after 15 days from miRcombo transfection was ∼11%, as evaluated by flow cytometry. Furthermore, a relevant percentage of miRcombo-transfected AHCFs (∼38%) displayed spontaneous calcium transients at 30 days post-transfection. Results evidenced the role of miRcombo transfection on triggering the trans differentiation of AHCFs into iCMs. Although further investigations are needed to achieve iCM maturation, early findings from this study pave the way toward new advanced therapies for human cardiac regeneration.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype

Paoletti

Divieto

Tarricone

et al. 2020

Front. Bioeng. Biotechnol.

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“…Delivery of ECM biomaterials is another effective strategy to promote cardiac regeneration and maintain heart function recovery 43 . Direct cardiac reprogramming offers a potential novel approach for restoring cardiac function, during which CFs could be converted into induced CM-like cells (iCMs) without first reverting them into stem cells 44 . Direct cardiac reprogramming can be achieved by the transduction of various cardiac-specific factors 45 .…”

Section: Cardiac Fibroblastsmentioning

confidence: 99%

The Roles of Noncardiomyocytes in Cardiac Remodeling

Yang

Liu

et al. 2020

Int. J. Biol. Sci.

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Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

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“…The recent development of cell-free, cardiac-fate direct reprogramming methods offers a dual advantage of reducing scar tissue while simultaneously generating new functional CMs without passing through a pluripotent stage [ 72 ]. Unlike iPSCs, direct reprogramming methods avoid the major pitfalls of iPSCs techniques including time-consuming cell conversion, the risk of genetic abnormalities, and tumorigenesis [ 73 , 74 ].…”

Section: Direct Cardiac Reprogramming For Heart Regenerationmentioning

confidence: 99%

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

Jiang

Liang

Huang

et al. 2020

IJMS

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Limited adult cardiac cell proliferation after cardiovascular disease, such as heart failure, hampers regeneration, resulting in a major loss of cardiomyocytes (CMs) at the site of injury. Recent studies in cellular reprogramming approaches have provided the opportunity to improve upon previous techniques used to regenerate damaged heart. Using these approaches, new CMs can be regenerated from differentiation of iPSCs (similar to embryonic stem cells), the direct reprogramming of fibroblasts [induced cardiomyocytes (iCMs)], or induced cardiac progenitors. Although these CMs have been shown to functionally repair infarcted heart, advancements in technology are still in the early stages of development in research laboratories. In this review, reprogramming-based approaches for generating CMs are briefly introduced and reviewed, and the challenges (including low efficiency, functional maturity, and safety issues) that hinder further translation of these approaches into a clinical setting are discussed. The creative and combined optimal methods to address these challenges are also summarized, with optimism that further investigation into tissue engineering, cardiac development signaling, and epigenetic mechanisms will help to establish methods that improve cell-reprogramming approaches for heart regeneration.

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Ameliorating the Fibrotic Remodeling of the Heart through Direct Cardiac Reprogramming

Cited by 24 publications

References 112 publications

MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype

MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype

The Roles of Noncardiomyocytes in Cardiac Remodeling

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

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