Critical Factors for Cardiac Reprogramming

Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158.
Circulation Research (Impact Factor: 11.02). 06/2012; 111(1):5-8. DOI: 10.1161/CIRCRESAHA.112.271452
Source: PubMed
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    • "Given the lack of a therapeutic approach to reverse the loss-of-functional myocardium, the development of efficient regenerative procedures is an urgent need in the field of modern cardiovascular research. As an alternative, a promising cell-free strategy is based on the use of small molecules or paracrine factors to stimulate cardiomyocyte proliferation or differentiation of resident cardiac cells [10] [11] [12]. Recently, a new class of small noncoding RNAs or microRNAs (miRNAs) were identified as important posttranscriptional inhibitors of gene expression through their ability to block the translation of messenger RNA (mRNA) [13]. "
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    ABSTRACT: miRNAs, a unique class of endogenous noncoding RNAs, are highly conserved across species, repress gene translation upon binding to mRNA, and thereby influence many biological processes. As such, they have been recently recognized as regulators of virtually all aspects of cardiac biology, from the development and cell lineage specification of different cell populations within the heart to the survival of cardiomyocytes under stress conditions. Various miRNAs have been recently established as powerful mediators of distinctive aspects in many cardiac disorders. For instance, acute myocardial infarction induces cardiac tissue necrosis and apoptosis but also initiates a pathological remodelling response of the left ventricle that includes hypertrophic growth of cardiomyocytes and fibrotic deposition of extracellular matrix components. In this regard, recent findings place various miRNAs as unquestionable contributing factors in the pathogenesis of cardiac disorders, thus begging the question of whether miRNA modulation could become a novel strategy for clinical intervention. In the present review, we aim to expose the latest mechanistic concepts regarding miRNA function within the context of CVD and analyse the reported roles of specific miRNAs in the different stages of left ventricular remodelling as well as their potential use as a new class of disease-modifying clinical options.
    Full-text · Article · Jul 2015
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    • "Quite recently, the so-called “re-programmed” fibroblast has been advanced as the preparation of choice for heterologous introduction into the compromised myocardium or other end-organs in the context of Regenerative Medicine approaches to Chronic Disease Management (Leri and Kajstura, 2012; Palpant and Murry, 2012; Qian et al., 2012; Song et al., 2012; Srivastava and Ieda, 2012; Miki et al., 2013). The fundamental principles of fibroblast isolation and reprogramming appear now to be well understood. "
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    ABSTRACT: In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct, significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na(+) current, INa. Some of the biophysical properties and molecular features suggest that this INa is due to expression of Nav 1.5, the same Na(+) channel α subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the "trigger" and the "substrate" components of cardiac rhythm disturbances. Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the α and β subunits of these Na(+) channel(s); (iii) to define the biophysical and pharmacological properties of this INa; (iv) to integrate the available multi-disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement. Our experimental findings confirm that a significant fraction (approximately 40-50%) of these human atrial myofibroblasts can express INa. However, our data suggest that INa may be generated by a combination of Nav 1.9, Nav 1.2, and Nav 1.5. Our results, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g., persistent atrial fibrillation.
    Full-text · Article · Aug 2014 · Frontiers in Physiology
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    • "In addition to the above, before introducing direct reprogramming in clinical trials, another limitation that needs to be considered is that the introduction of viruses into human subjects is generally undesirable; the mechanisms of viral action in humans remain unclear and such usage could introduce unpredictable factors that could lead to infections or even cancer.72 This substantiates the need to consider other means of delivering reprogramming factors, such as, via specially modified RNA or small molecules.73 Last but not of least importance, certain human cell types, such as fibroblasts, are usually more difficult to reprogram compared, for example, to mouse fibroblasts.74 "
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    ABSTRACT: The procedure of using mature, fully differentiated cells and inducing them toward other cell types while bypassing an intermediate pluripotent state is termed direct reprogramming. Avoiding the pluripotent stage during cellular conversions can be achieved either through ectopic expression of lineage-specific factors (transdifferentiation) or a direct reprogramming process that involves partial reprogramming toward the pluripotent stage. Latest advances in the field seek to alleviate concerns that include teratoma formation or retroviral usage when it comes to delivering reprogramming factors to cells. They also seek to improve efficacy and efficiency of cellular conversion, both in vitro and in vivo. The final products of this reprogramming approach could be then directly implemented in regenerative and personalized medicine.
    Full-text · Article · Feb 2014 · Stem Cells and Cloning: Advances and Applications
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