We searched PubMed for published articles with the terms “cardiovascular disease”, “heart failure”, “cardiac regeneration”, “cardiac progenitor”, “stem cell”, and “stem cell therapy”. Most selected publications were published in the past 5 years. Older publications were included if they were well regarded or widely referenced. We also included references listed in articles identified in the initial searches, and reports from governmental organisations. The date of the last search was Nov 30,
SeriesTowards regenerative therapy for cardiac disease
Introduction
Heart failure is one of the key causes of morbidity and mortality worldwide.1 The effects of heart failure are growing very rapidly, especially in developing countries.2 Available medical and device-based therapies can ameliorate the effects of heart failure, but cannot reverse the loss of functional myocardium, which is the underlying cause of the problem.3 The only available cure for advanced heart failure is orthotopic heart transplantation, which is not a viable strategy in the general population because of a relative absence of donor hearts.4 Heart failure is thus evolving into a global epidemic for which medicine does not have an available solution. Design of an efficacious regenerative therapeutic strategy has therefore become a holy grail of modern cardiovascular science. Recent breakthroughs in stem cell biology provide large strides toward this goal. This report discusses key opportunities and challenges in movement from academic stem cell biology towards the development of cardiovascular regenerative therapy.
Section snippets
Attempted cardiac regeneration with non-cardiac progenitor cells
The severity of heart failure and the inability of available treatments to abrogate its effects have spurred intense interest in cardiac regeneration. Several organs, notably the liver, have clinically relevant regeneration after injury.5 Although cardiac regeneration is reported in lower vertebrates such as amphibians and zebrafish, equivalent regenerative capacity is not possessed by adult mammals.6, 7 Cardiomyocyte proliferation is present in neonatal mice, but diminishes rapidly after birth,
Endogenous cardiac progenitor cells
Augmentation of endogenous regenerative activity is a compelling strategy for cardiac repair. In theory, such amplification can be achieved with two distinct approaches. One approach would be to stimulate expansion of cardiomyocytes or putative cardiac progenitor cells with a drug or paracrine factor, in the same way that erythropoietin is given to stimulate bone marrow progenitor cells to produce erythrocytes. The second approach involves propagation of cardiac cells with regenerative
Genetic fate mapping and endogenous cardiac progenitor cells
The search for cardiac cells and paracrine factors that are capable of triggering cardiac repair has been challenging. Further progress will need more precise definitions of the phenotypes and biological roles of relevant cell populations. Use of genetic fate mapping to study embryonic cardiogenesis has eased the definition of progenitor populations and helped establish their roles in forming of discrete cardiac structures.
The heart contains a complex array of structures, including muscle,
The promise of induced pluripotent stem cells
Even if the phenotypes of cardiac cells with regenerative potential can be better defined, their rarity might make it difficult to generate enough cells to produce a clinically meaningful effect. Embryonic stem cells are an attractive source of starting material for cell-based therapies, mainly because they are self-renewing pluripotent cells that can be differentiated into tissues from all three germ layers.57 Cardiomyocytes produced from mouse embryonic stem cells in vitro are closer to the
Paracrine factors in cardiac regeneration
Paracrine factors, notably those in the renin–angiotensin system, have key roles in cardiac pathophysiological mechanisms.70 The benefit associated with bone marrow cell therapy might be attributable to paracrine factors, but neither the identity nor the actions of these putative factors are known. Several possible activities have been proposed, including activation of putative endogenous cardiac progenitor cells, direct stimulation of cardiomyocyte division, and modification of the tissue
Delivery of regenerative therapy
A safe, effective, and practical delivery system is crucial to the success of cardiac regenerative therapy. Such a platform would have to ensure reliable delivery of a sufficient amount of the therapeutics to trigger regeneration, have good visualisation of the target area, and provide specific delivery to the target area with minimal off-target delivery and little or no risk of haematogenous dissemination.72 Several delivery techniques have been reported, ranging from direct intramyocardial
Cardiac tissue engineering
Successful reconstitution of damaged cardiac tissue cannot rely solely on regeneration of cardiomyocytes because the architecture of myocardium is complex. Cardiomyocytes in the adult heart are oriented end-to-end in fibres, which are woven into anisotropically oriented sheets whose organisation forms the basis for chamber contraction. Among these sheets are complex webs of fibroblasts, blood vessels, and conduction-system tissue. Spatial organisation of these cells during embryogenesis is
Perspectives
The heart is made up of a complex mosaic of distinct anatomical elements that are substantially disrupted in cardiac injury. Because of this complexity, restoration of cardiac function would need recreation of the native architecture of the heart, not just regeneration of one cell type. An ideal cardiac regenerative therapy would possess a key cell and paracrine factor combination, a cardiac tissue niche optimised to enhance cell engraftment and differentiation, and a safe, minimally invasive
Search strategy and selection criteria
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Cited by (194)
Engineering stem cell therapeutics for cardiac repair
2022, Journal of Molecular and Cellular CardiologyUmbilical cord mesenchymal stromal cells engraft and transdifferentiate into cardiomyocyte-like cells following acute myocardial ischemia⋆
2020, Acta HistochemicaCitation Excerpt :In this study, we tested the efficacy of intramyocardial cell administration following an acute MI intervention, after which the animals were followed up for 3 weeks. We directly transplanted cells around the ischemic region, a more direct route of delivery, which noticeably inhibited the cell loss after transplantation since many transplanted cells either diffuse throughout the body with the circulatory system as immunologically rejected, do not find a proper microenvironment and become trapped in the pulmonary vasculature (Ptaszek et al., 2012). Yannarelli et al. recorded that cardiac function improved when hUC-perivascular cells (PVCs) were administered intramyocardially, whereas observed no improvement in cardiac function when the same type and number of cells were given by IV (intravenous) infusion (Yannarelli et al., 2013).
Advances in regenerative therapy: A review of the literature and future directions
2020, Regenerative Therapy