Current Stem Cell Research & Therapy - Volume 15, Issue 8, 2020

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality globally, and traditional pharmaceutical and surgical interventions delay the progression of CVDs. Recently, stem cell therapy has emerged as a promising candidate for treating and preventing heart failure. Increasing efforts have been devoted towards the exploration and identification of potential cell types to repair the injured heart, such as skeletal myoblasts, embryonic, induced pluripotent, bone marrowderived, mesenchymal, and resident cardiac stem cells. In addition, direct reprogramming of cardiac fibroblasts into cardiomyocytes represents a novel approach to cardiac regeneration. Herein, we summarize the recent progress in the use of various cell types for cardiac regeneration and discuss major challenges and future perspectives of cell-based therapies for CVDs.

Background: Substantial evidences support the hypothesis that the epicardium has a role in cardiac repair and regeneration in part providing, by epithelial to mesenchymal transition (EMT), progenitor cells that differentiate into cardiac cell types and in part releasing paracrine factors that contribute to cardiac repair. Besides cell contribution, a significant paracrine communication occurs between the epicardium and the myocardium that improves the whole regenerative response. Signaling pathways underlying this communication are multiple as well as soluble factors involved in cardiac repair and secreted both by myocardial and epicardial cells. Most recently, extracellular vesicles, i.e. exosomes, that accumulate in the pericardial fluid (PF) and are able to transport bioactive molecules (cytosolic proteins, mRNAs, miRNAs and other non-coding RNAs), have been also identified as potential mediators of epicardial-mediated repair following myocardial injury. Conclusion: This mini-review provides an overview of the epicardial-myocardial signaling in regulating cardiac repair in ischemic heart diseases. Indeed, a detailed understanding of the crosstalk between myocardial and epicardial cells and how paracrine mechanisms are involved in the context of ischemic heart diseases would be of tremendous help in developing novel therapeutic approaches to promote cardiomyocytes survival and heart regeneration following myocardial infarction (MI).

Exosomes and biomimetic nanoparticles have great potential to develop into a wide-scale therapeutic platform within the regenerative medicine industry. Exosomes, a subgroup of EVs with diameter ranging from 30-100 nm, have recently gained attention as an innovative approach for the treatment of various diseases, including heart disease. Their beneficial factors and regenerative properties can be contrasted with various cell types. Various biomimetic nanoparticles have also emerged as a unique platform in regenerative medicine. Biomimetic nanoparticles are a drug delivery platform, which have the ability to contain both biological and fabricated components to improve therapeutic efficiency and targeting. The novelty of these platforms holds promise for future clinical translation upon further investigation. In order for both exosome therapeutics and biomimetic nanoparticles to translate into large-scale clinical treatment, numerous factors must first be considered and improved. Standardization of different protocols, from exosome isolation to storage conditions, must be optimized to ensure batches are pure. Standardization is also important to ensure no variability in this process across studies, thus making it easier to interpret data across different disease models and treatments. Expansion of clinical trials incorporating both biomimetic nanoparticles and exosomes will require a standardization of fabrication and isolation techniques, as well as stricter regulations to ensure reproducibility across various studies and disease models. This review will summarize current research on exosome therapeutics and the application of biomimetic nanoparticles in cardiac regenerative medicine, as well as applications for exosome expansion and delivery on a large clinical scale.

Although the lack of a robust cardiomyocyte proliferative response has been considered to be a crucial determinant of cardiac pathology and Heart Failure in adult mammalians, the emerging picture is that myocardial regeneration is a complex phenotype involving many actors, including acute cellular senescence and inflammation. However, three major and interconnected events occur in response to tissue injury: loss of protein homeostasis, accumulation of dysfunctional mitochondria and chronic inflammation. These events blunt the reparative response of the heart, are associated with the accumulation of chronically senescent cells and progressively lead to cardiac dysfunction. Therefore, it is crucial to understand which are the pivotal players of this process, in order to devise strategies aimed at reducing the occurrence of chronic cell senescence in the heart in vivo.

Nowadays, cardiac regeneration is an emerging topic in the cardiovascular field because of the compelling need for effective therapies for repairing or replacing cardiac tissue damaged by pathological or physiological conditions. Indeed, irreversible myocardial remodeling which follows acute myocardial infarction represents a serious burden of this century. In this context, a great improvement in pharmacological and interventional techniques is accompanied by a big challenge of cardiac regenerative medicine. In the last 20 years, several clinical trials tried to investigate the role of different types of stem cells in promoting cardiac repair. However, the promising results obtained in the preclinical trials have not yet been reproduced in patients. Thus, the development of novel strategies to improve stem cell efficiency became imperative. Here, an overview of the more recent cell types proposed for cardiac regeneration is presented, together with the most interesting approaches to enhance cell regenerative potential as well as cell-free approaches.

Heart failure is a significant source of morbidity and mortality around the world. Recently, cell therapy has garnered much attention as a means for improving cardiac function after injury. Despite years of study, a growing list of failed efficacy trials has led many to question the translatability of preclinical work. In this review, we critically evaluate the evidence supporting the need for transplanted cells to engraft and persist in the impaired heart (the cell engraftment hypothesis). We explore how the complex interplay between cell retention, persistence and paracrine potency explains many of the recent cell treatment outcomes. Through this discussion, we outline a framework to understand how future approaches will optimize and personalize the methods, payloads and timing of cardiac cell delivery for the millions of patients worldwide suffering from heart failure.

Large scale projects such as FANTOM and ENCODE led to a revolution in our comprehension of the mammalian transcriptomes by revealing that ~53% of the produced RNAs do not encode for proteins. These transcripts, defined as noncoding RNAs (ncRNAs), constitute a heterogeneous group of molecules which can be categorized in two main classes, namely small and long, according to their length. In animals, the first-class includes Piwi-interacting RNAs (piRNAs), small interfering RNAs (siRNAs) and microRNAs (miRNAs). Among them, the best-characterized subgroup is represented by miRNAs, which are known to regulate gene expression largely at the post-transcriptional level. In contrast, long noncoding RNAs (lncRNAs) represent a more heterogeneous group of > 200 nucleotides long transcripts, that act through a variety of mechanisms at both transcriptional and posttranscriptional level. Here, we discuss how miRNAs and lncRNAs are emerging as pivotal regulators of cardiac muscle development and how the alteration of ncRNA expression was seen to disturb the physiology of all the different cell types forming the cardiac tissue. Particular emphasis is given to those species that are expressed and are known to regulate the capacity of cardiac progenitor cells (CPCs), currently used in regenerative medicine protocols, to proliferate and differentiate. Understanding how the ncRNAmediated circuitries regulate heart homeostasis is one of the research areas expected to have a high impact, improving the therapeutic efficacy of stem/progenitor-cells treatments for translation into clinical applications.