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International Journal of Stem cell Research and Therapy





DOI: 10.23937/2469-570X/1410027



Epigenetics, Ethnicity, Bioinformatics and Nanotechnology Opening Frontiers in Cardiac Medicine

Janet L. Paluh*


State University of New York Polytechnic Institute, Colleges of Nanoscale Science and Engineering, Nanobioscience, Albany, NY 12203, USA


*Corresponding author: Janet L. Paluh, PhD, SUNY Polytechnic Institute, NanoFab East, room 4424, 257 Fuller Road, Albany, NY 12203, USA, Tel: 518-956-7047; Fax: 518-437-8687; E-mail: jpaluh@sunypoly.edu
Int J Stem Cell Res Ther, IJSCRT-3-027, (Volume 3, Issue 1), Short Review; ISSN: 2469-570X
Received: December 31, 2015 | Accepted: March 26, 2016 | Published: March 30, 2016
Citation: Paluh JL (2016) Epigenetics, Ethnicity, Bioinformatics and Nanotechnology Opening Frontiers in Cardiac Medicine. Int J Stem Cell Res Ther 3:027. 10.23937/2469-570X/1410027
Copyright: © 2016 Paluh JL. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

Stem cell based therapy directed towards improving the long-term therapeutic outcome of heart disease in many regards remains in its infancy. Although strategies with bone marrow derived stem cells have been prevalent in clinical trials, other stem cell resources are less explored. The ability to use reprogrammed somatic cells for patient-optimized therapies, either from direct reprogramming to cardiac lineage or reprogramming first to pluripotent stem cells, requires expanding our understanding of how the epigenetic landscape affects downstream differentiation into cardiomyocytes or other specialized cardiac cells. Helping to fill this information gap are advances in whole genome analysis and bioinformatics, coupled with in vitro differentiation protocols further optimized through the use of nanotechnology to aid in biomimetic representation of the cardiogenic niche. Nanotechnology is also providing new functional assays for comparative quantitative assessment of derived cells. The interdisciplinary juggernaut being applied to understanding cardiac development, regulatory pathways and transitions, roles of ethnicity, and disease pathways is expected to propel the field within the next decade with new promise for therapeutic potential to address the devastating morbid diseases associated with cardiovascular diseases.


Keywords

iPSC, ESC, Cardiovascular, Cardiomyocytes, Differentiation, Reprogramming, SNP


Short Review

The impact of heart disease on long-term survival has remained largely unchanged for over two decades, even described to have poorer life expectancy than many cancers [1]. Globally cardiovascular disease (CVD) remains the number one cause of death according the World Health Organization (WHO), representing 17.5 million people or 31 percent of all global deaths. The 2015 update by the American Heart Association (AHA) in conjunction with the Center for Disease Control (CDC), National Institutes of Health (NIH) and other agencies emphasizes the immense global health and economic burdens of cardiovascular disease (CVD) with stroke, congenital heart disease, heart failure, and rhythm disorders being among major clinical disease conditions. In 2011, 1 in 9 deaths mentioned heart failure (HF) similar to levels in 1995. Coronary heart disease alone resulted in 1 in 7 deaths in the US in 2011, or 375,295 reported deaths, including myocardial infarctions. In the US a coronary event occurs every 34 seconds, resulting in death every 84 seconds. Despite longer initial survival the poor overall long-term prognosis is concerning. Although natural repair and regeneration mechanisms exist for the heart, these are still being explored but decrease with increasing age [2,3]. Significant hope lies in stem cell efforts to bring treatment solutions, initially in terms of cardiomyoplasty and other cell therapies for myocardial infarctions [4], but beyond this to expand on fundamental concepts of heart development and disease.

In cardiac ischemic injury, the loss of cardiomyocytes through apoptosis, along with activation of inflammatory and repair responses that include remodeling of the injured area with myofibroblast tissue play critical roles in heart failure. To restore electromechanical action of ventricular muscle and pumping activity lost in myocardial infarctions requires replacing myofibroblast scar tissue with new cardiomyocytes [5]. The successful derivation of mammalian cardiomyocytes from stem cells in vitro has been explored from adult cardiac stem cells, pluripotent embryonic and induced pluripotent stem cells [6-8] and induced cardiac direct reprogramming [9,10] approaches. Clinical trials have relied primarily on bone marrow derived stem cells and have seen minimal or no effect [11], bringing into question whether bone marrow represents the best source of stem cells for cardiac therapies [12]. Clinical trials that use alternate stem cell sources, such as endogenous CSCs to address ischemic cardiomyopathy [13-15] have produced encouraging results with reduced infarct size and improved left ventricle function suggesting therapeutic regeneration without side effects. In addition the first world hESC clinical trial for cardiac repair is underway, initiated in 2014, to address left ventricular systolic dysfunction with contraction reduced at or below 35% [16]. A challenge in comparing effectiveness of non-endogenous stem cell sources in clinical trials, is that not all stem cell derived cardiomyocyte sources are characterized at the transcriptome or epigenome level of detail which is expected to include relevant information to predict interactions with other cells in vivo that may influence integration success.

The ability of stem cell studies to inform on signaling pathways underlying mesoderm and cardiac mesoderm differentiation [17] as well as heart morphogenetic development and heart disease models that impact cardiac therapy [18] reflect key aspects of a field that is clearly untapped in potential. The application of bioinformatics to cardiogenesis continues to be critical to identify numerous contributing pathways that underlie precise temporal transitions operating in heart development. In addition to gene signatures and transcription factor cascades [19], small nucleotide polymorphisms (SNPs) have been shown to impact cardiac therapies [20], including ethnic risk factors [21] and are important in optimizing personalized medical intervention. The availability of new resources of ethnically diverse stem cell lines [22] will allow opportunities to expand our knowledge of contributing genes and pathways relevant to ethnic populations. To what extent embryonic developmental pathways and cell fate decisions are recapitulated by in vitro manipulation of stem cells is still being explored [23]. In part these questions are being addressed through whole genome analysis and bioinformatics, including added regulatory detail in transcriptome and epigenetics during cardiac developmental transitions [18]. Cross-disciplinary nanotechnology applications include design of custom microwell scaffolds for generating uniformly sized 3D cardiospheres and differentiation intermediates, such as embryoid bodies [22,24], new methods for visually quantifying beating in vitro [25] and opportunities for micro electromechanical systems (MEMS), drug screening platforms, scaffolds and cell delivery [26-28].

In the developing embryo the heart is the first organ to become functional and cardiac precursor cells are present even before gastrulation and tri-lineage germ layer formation into mesoderm, ectoderm and endoderm [29]. Cardiomyocytes that derive from the mesoderm are preceded by several developmental morphogenic stages that include formation of the primitive streak, the epithelial-mesenchymal transition and formation of mesendoderm before lineage separation into endoderm and mesoderm. In addition to specialized cardiomyocytes, multiple cell types develop from mesoderm including bone and cartilage, adipose tissue, striated and smooth muscle, blood and lymph vessels and cells, and specialized cells for kidney, spleen and gonad function as well as serous membrane epithelium [30,31]. The ability of cells during development to naturally integrate into specific tissue, organ and systemic domains suggests that we should be able to control these events in myocardial repair, given the appropriate niche and temporal gene expression information, analogous to the use of the early embryonic environment and pathways to inform on reprogramming control genes in iPSC technology [32,33].

How the initial epigenetic landscape impacts potential for cardiogenesis and cardiomyocyte formation has not yet been well explored along with additional patient factors of age, ethnicity and gender due to a gap in resources. A study underway in my laboratory is exploring transcriptome and epigenome profiles of ethnic replicate iPSC lines generated in house [19] from self-declared Hispanic-Latino, African American and Asian ethnicities. Of interest is the ability to predict efficiency of cardiomyocyte formation while also monitoring formation of other mesodermal-derived cells as well as cells of endoderm and ectoderm origin. We observed that the stochastic nature of reprogramming which generates differences in gene expression even amongst replicate lines derived from a single somatic cell source, can either have little impact or generate differences in differentiation to beating cardiomyocytes while not affecting other cell types. Advancing the success of stem cell derived cardiomyocytes in clinical trials, may well rely on a better understanding of the transcriptomes and epigenomes of the cells we classify roughly as identical. By co-evaluating transcriptome, epigenetic and patient specific differences of ethnicity, age and gender as well as disease history we can identify relevant cross-pathway signaling cascades in cardiomyocyte formation with the goal to overcome integration and remodeling barriers that bear on heart disease and personalized biomedical therapies.

The combined interdisciplinary understanding of cardiogenesis that is being obtained through stem cell studies that bring into consideration epigenetic landscapes, ethnicity, optimized nanotechnology, and bioinformatics profiling (Figure 1) will set a comprehensive standard for broader stem cell based therapies. The next decade is expected to bring a significant leap in our understanding of normal cardiogenesis and disease in a patient diverse population and bolster the hope for improved therapeutic outcomes.


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Figure 1: An interdisciplinary approach to stem cell therapies in cardiac health. View Figure 1



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Acknowledgement

Pluripotent stem cell and cardiomyocyte research on ethnically diverse lines characterized in the Paluh lab was supported in part by the New York State stem cell agency NYSTEM, award C026186.


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