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      Naturally Engineered Maturation of Cardiomyocytes.

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          Abstract

          Ischemic heart disease remains one of the most prominent causes of mortalities worldwide with heart transplantation being the gold-standard treatment option. However, due to the major limitations associated with heart transplants, such as an inadequate supply and heart rejection, there remains a significant clinical need for a viable cardiac regenerative therapy to restore native myocardial function. Over the course of the previous several decades, researchers have made prominent advances in the field of cardiac regeneration with the creation of in vitro human pluripotent stem cell-derived cardiomyocyte tissue engineered constructs. However, these engineered constructs exhibit a functionally immature, disorganized, fetal-like phenotype that is not equivalent physiologically to native adult cardiac tissue. Due to this major limitation, many recent studies have investigated approaches to improve pluripotent stem cell-derived cardiomyocyte maturation to close this large functionality gap between engineered and native cardiac tissue. This review integrates the natural developmental mechanisms of cardiomyocyte structural and functional maturation. The variety of ways researchers have attempted to improve cardiomyocyte maturation in vitro by mimicking natural development, known as natural engineering, is readily discussed. The main focus of this review involves the synergistic role of electrical and mechanical stimulation, extracellular matrix interactions, and non-cardiomyocyte interactions in facilitating cardiomyocyte maturation. Overall, even with these current natural engineering approaches, pluripotent stem cell-derived cardiomyocytes within three-dimensional engineered heart tissue still remain mostly within the early to late fetal stages of cardiomyocyte maturity. Therefore, although the end goal is to achieve adult phenotypic maturity, more emphasis must be placed on elucidating how the in vivo fetal microenvironment drives cardiomyocyte maturation. This information can then be utilized to develop natural engineering approaches that can emulate this fetal microenvironment and thus make prominent progress in pluripotent stem cell-derived maturity toward a more clinically relevant model for cardiac regeneration.

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          Most cited references187

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          The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.

          The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of cardiomyocyte proliferation-based therapeutic approaches. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.

            The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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              Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.

              Cardiac hypertrophy can be defined as an increase in heart mass. Pathological cardiac hypertrophy (heart growth that occurs in settings of disease, e.g. hypertension) is a key risk factor for heart failure. Pathological hypertrophy is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. In contrast, physiological cardiac hypertrophy (heart growth that occurs in response to chronic exercise training, i.e. the 'athlete's heart') is reversible and is characterized by normal cardiac morphology (i.e. no fibrosis or apoptosis) and normal or enhanced cardiac function. Given that there are clear functional, structural, metabolic and molecular differences between pathological and physiological hypertrophy, a key question in cardiovascular medicine is whether mechanisms responsible for enhancing function of the athlete's heart can be exploited to benefit patients with pathological hypertrophy and heart failure. This review summarizes key experimental findings that have contributed to our understanding of pathological and physiological heart growth. In particular, we focus on signaling pathways that play a causal role in the development of pathological and physiological hypertrophy. We discuss molecular mechanisms associated with features of cardiac hypertrophy, including protein synthesis, sarcomeric organization, fibrosis, cell death and energy metabolism and provide a summary of profiling studies that have examined genes, microRNAs and proteins that are differentially expressed in models of pathological and physiological hypertrophy. How gender and sex hormones affect cardiac hypertrophy is also discussed. Finally, we explore how knowledge of molecular mechanisms underlying pathological and physiological hypertrophy may influence therapeutic strategies for the treatment of cardiovascular disease and heart failure. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Front Cell Dev Biol
                Frontiers in cell and developmental biology
                Frontiers Media SA
                2296-634X
                2017
                : 5
                Affiliations
                [1 ] Meinig School of Biomedical Engineering, Cornell UniversityIthaca, NY, USA.
                Article
                10.3389/fcell.2017.00050
                5418234
                28529939
                78689ad6-3373-4bff-b18d-8f3d76bbf78e
                History

                cardiomyocyte maturation,electrical stimulation,engineered heart tissue,extracellular matrix signaling,mechanical stimulation,natural engineering,non-cardiomyocyte signaling

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