Evolving challenges in promoting stem cell based cardiovascular repair and regeneration

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Background

Cardiovascular disease is a leading cause of significant morbidity and mortality in the United States as well as world-wide. Mammalian heart, including human heart has been considered as a post-mitotic organ composed of highly specialized and terminally differentiated cardiac myocytes. These mammalian cardiac myocytes have traditionally been considered as post-mitotic cells with an extremely low or practically no capacity to divide and regenerate. Recently, it has been shown that mammalian cardiac muscle has limited proliferative potential and restricted regeneration within the damaged myocardium. Hence, it may be beneficial to explore the limited natural capacity of mammalian cardiac muscle regeneration in light of the spontaneous cardiac muscle regeneration observed in the lower vertebrates such as fish and amphibians (cardiovascular genetics). The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of exogenous embryonic- and/or adult-derived stem cells as well as the endogenous cardiac stem/progenitor cells as possible sources for regenerating myocardium. Using stem cells, it has been possible to stimulate mammalian cardiac muscle regeneration and researchers have investigated the potential of various multi- and/or pluri-potential stem cells, such as MSCs, ESCs, iPSCs and CPCs (cardiovascular differentiation of stem cells). A major issue that remains to be addressed is the extent to which introduced stem cells and/or endogenous cardiac progenitor cells contribute directly to the formation of neo-cardiomyocytes versus their contribution to and/or stimulation of an enhanced local vascular response, which in turn may act as a supportive microenvironment for regeneration. Use of adult stem cells (MSCs/iPSCs) in the stimulation of mammalian cardiac muscle regeneration is in its infancy, and to date, it has been difficult to determine the efficacy of procedures that have been employed. The outstanding question remains whether stem cells derived from the bone marrow or some other location within or outside of the heart can populate a region of myocardial damage and transform into tissue-specific cells and also exhibit functional synchronization (stem cell based cardiomyoplasty). As a result, this necessitates the development of appropriate in vitro 3-D model of cardiomyogenesis and prompts the development of a 3-D cardiac muscle construct for tissue engineering purposes, especially using the postnatal/adult stem cells, MSCs and/or iPSCs for personalized medicine. Restricted myocardial regeneration after tissue injury and shortage of organs for transplantation are the principal constraints of conventional therapies. Organ tissue engineering, including cardiovascular tissues, has been an area of intense investigation. The major challenge to these approaches has been the inability to vascularize and perfuse the in vitro engineered tissue constructs. Attempts to provide oxygen and nutrients to the cells contained in the biomaterial constructs have varying degrees of success. Engineering a tissue of clinically relevant magnitude requires the formation of extensive and stable microvascular networks within the tissue. Since most in vitro engineered tissue constructs do not contain the intricate microvascular structures of native tissue, the cells contained in scaffolds heavily rely on simple diffusion for oxygenation. In addition, the interaction of the cells of the host and construct has not been well characterized (cardiovascular tissue engineering, bionanotechnology). Given these shortcomings, this ‘Frontiers Research Proposal’ is aimed ‘to address how to develop a three-dimensional (3-D) model of vascularized cardiac tissue to study the concurrent temporal and spatial regulation of cardiomyogenesis in the context of postnatal de novo Vasculogenesis during stem cell cardiac regeneration’. The fundamental problem of cardiac repair and regeneration can only be addressed by means of multidisciplinary knowledge and approach. Therefore, this ‘Frontiers in Research Topic’ is targeted at garnering the cutting-edge knowledge and technical advances in the field of “Stem Cell Biology, Tissue Engineering and Regenerative Medicine” and disseminating that invaluable knowledge in a timely manner to greater scientific community. In order to accelerate and/or tackle one of the most fundamental problems facing cardiac therapy, i.e. to repair and/or regenerate the damaged myocardium during heart failure.

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