Stem Cells And Their Role In Cardiac Regeneration

Introduction.

Cardiovascular disease has been the leading reason behind death amongst individuals of all ages for many years, accounting for over 30 percent of death in populations across the world. These statistics have persisted, despite the advancement in health care facilities and technologies.

The discovery of the pluripotent stem cells that are capable differentiating into different kinds of cells, and may conjointly divide in self-renewal to supply additional of identical sort of stem cell; has channeled a substantial quantity of human resources to the exploitation of the chances of cardiac tissue regeneration, using these cells.

More specific clusters of cells have been discovered over time, including the cardiac progenitor cells which are an endogenous cluster of cells that have been discovered in various niches within the cardiac tissue. These groups of cells that were initially discovered in lower mammals like the mice are a significant topic of interest inside the biomedical universe, and further research has led to the discovery of the various groups present within the human heart, which are involved in numerous functions.

These cells have been found to play necessary roles in such cardiac pathology as myocardial infarction, roles including secretion of extracellular vesicles, which are concerned with the inhibition of cardiomyocyte cell death.

Cardiac progenitor cells have also been proposed to have the capability to proliferate and differentiate into mature cardiomyocytes, which has made the study of the potency of these cells momentous, as they bring a promise of the possibility of cardiac regeneration.

Analysis and discussion

Cardiovascular disease is currently top on the hierarchy of causes of death in the world, an estimated 17.9 million individuals died from cardiovascular diseases in 2016, being responsible for thirty-one percent of all world deaths. Of these deaths, eighty-fifth are due to heart attack and stroke [2], and acute myocardial infarction (MI) is associated with a 30 percent death rate [3].

Acute myocardial infarction is taken into account as the most common cardiovascular disease, and it happens because of a shortage or stoppage of the blood provision to the cardiomyocytes, and also the resultant lack of oxygen and different nutrients needed for traditional functioning of the heart would cause a series of events leading to cell death, and various inflammatory responses that ultimately induce cardiomyocytes damage. This series of events lead to the formation of scar tissue, and stiffness of cardiac muscles which would prevent normal contraction of the chambers of the heart. Heart failure ultimately occurs when the heart is unable to pump the sufficient amount of blood required by the various organs of the human organism, and this eventually leads to death.

Though medical and surgical treatments such as pharmacotherapy, percutaneous coronary intervention (PCI), and surgical management will considerably improve patient outcomes and reverse viable ischaemic tissue, no current treatment is in a position to form new contractile tissue or regenerate lost heart muscle [5]. the foremost factious approach to treating heart failure has therefore been the heart transplant procedure, which itself is faced with varied challenges and drawbacks as wells as the danger of the rejection by the immune cells of the recipient which creates the requirement for the recipient to remain on immunosuppressants for the rest of their lives (consequently reducing their resistance for antigens), and a restricted quantity of donors.

Since its discovery, an oversized range of clinical trials have shown stem cell therapy to be a promising therapeutic approach for the treatment of cardiovascular diseases. Since the primary transplantation into human patients, several stem cell types have been applied in this field, including bone marrow-derived stem cells, cardiac progenitors as well as embryonic stem cells and their descendants [4].

Stem cells are cells that will differentiate into different kinds of cells, and may conjointly divide in self-renewal to produce additional of identical sorts of stem cells. In mammals, there are 2 broad kinds of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts in early embryonic development, and adult stem cells, which are found in various tissues of totally developed mammals. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells of the germ layers—ectoderm, endoderm and mesoderm —and also maintain the traditional turnover of regenerative organs, such as blood, skin, or intestinal tissues [1].

Cardiac progenitor cells (CPCs)

They are a heterogeneous cluster of cells distributed throughout the heart, (including the atria, ventricles, and epicardium or pericardium) [7], and studies have evidenced the involvement of these cells in the regulation of myocyte turnover, however there’s quite a raging controversy over their capability to regenerate lost myocardial tissue. Since 2003, when the presence of self-replicating, clonogenic, multipotent c-kit+ cells within the heart which could give rise to cardiomyocytes, smooth muscle cells, endothelial cells, and angiogenic cells was identified, various studies have shown that there exists a subpopulation of various classes of cardiac progenitor cells. Additionally, to ckit+ cells, different sorts of cardiac progenitor cells include, Sca-1+ cells, IGF1R+ cells, Isl1+ cells, cardiosphere-derived cells (CDCs), cardiac mesangioblasts, cardiac side population cells, and epicardial progenitors, all of which show different but overlapping surface markers [6]. Encouraging results whereby c-Kit+ CPCs improved left ventricular chamber pathology and remodeling in numerous pre-clinical models of post-myocardial infarction cardiomyopathy have paved the road for Cardiac Stem cell implantation in Patients with Ischaemic Cardiomyopathy (SCIPIO), the first clinical trial of CPCs [7].

SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit+ cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG) [8].

In humans, studies have tested the employment of c-kit+ and CDCs, and initial clinical test results are encouraging. The SCIPIO phase I clinical attempt showed improved left ventricular ejection fraction and decreased infarct size after four and twelve month follow-ups post intracoronary administration of autologous c-kit + cardiac stem cells in ischemic cardiomyopathy patients undergoing coronary artery bypass graft (CABG). In first phase of the CADUCEUS trial, autologous cardiosphere derived cells were injected after myocardial infarction into the artery related with the infarction and this increased regional contractility and viable heart tissue, and concurrently decreased scar mass at the sixth-month magnetic resonance imaging follow-up, however, the increase in left ventricular ejection fraction was quite insignificant [6].

The cardiac progenitor cells are found to be involved in the paracrine release of certain molecules, resulting in the restoration of cardiac tissue after damage. They also support by facilitating the development of new blood vessels to supply the damaged myocardium [9]. An experiment by Ibrahim et al showed that exosomes from cardiac progenitor cells brought about development of new blood vessels and improved cardiomyocyte proliferation. This experiment also showed that blocking the release of exosomes resulted in the inefficiency of the cardiac progenitor cells [9].

Despite the uncertainty surrounding the theories and experiments on the potential of the cardiac progenitor cells to proliferate and bring about the regeneration of damaged cardiac tissue, it so far has been recognized as the most promising stem cell-related solution for heart failure due to damaged cardiac tissue, as it appears to have the highest regenerative potential. Its application for the treatment of various cardiovascular diseases is on the rise, and more investment and effort is going into the perfection of this method. By May 2017, it was reported close to twenty-one cardiac progenitor-based clinical tests have been successfully enrolled for patients [9] and the application of the cardiac progenitor cells for the treatment of cardiovascular disease gradually is becoming a reality that could change the medical universe permanently.

Human embryonic stem cells (hESCs)

Human embryonic stem cells are pluripotent cells, the term “pluripotent” describes their capability to differentiate into any embryonic cell type, they are also characterized by self-renewal capabilities.

This group of cells has been employed in various clinical and experimental attempts to regenerate various tissues of the human organism. The progress of this procedure has been quite auspicious, due to the rate of success encountered in animal models, including nonhuman primates [10]. A study by Liu et al that involved the transplantation of about 750 million cryopreserved cardiomyocytes acquired from human embryonic stem cells into macaque monkeys with massive infractions in their myocardium showed an improvement of left ventricular ejection fraction by about 10.6 which is about 0.9 percent versus 2.5 which is about 0.8 percent in controls, within a one month period. The same study records an addition of 12.4 percent improvement in treated vs. a 3.5 percent deterioration in controls within three months. Grafts averaged 11.6 percent of infarct size, formed electromechanical junctions with the monkeys heart, and by the third month contained about 99 percent ventricular myocytes [10]. Liu et al confirm according to their data that the use of human myocardium derived from human embryonic stem cells to remuscularize the infarcted macaque monkey heart provides long-lasting improvement in left ventricular function; they further acknowledge the capacity of pliuripotent stem cells to form teratomas but however account that no such situations were recorded in their processes. This report also acknowledges that a subset of macaque monkeys used in this procedure experienced graft-associated ventricular arrhythmias, which appeared to have emanated from a point-source playing the role as an ectopic pacemaker.

Another research was carried out using guinea pig models to show that human embryonic stem cells cardiomyocytes grafts in injured hearts could serve protective functions against arrhythmias and have the capability to contract synchronously with the guinea pig’s cardiac muscles [12]. Injured hearts with human embryonic stem cell cardiomyocyte grafts show an elevated mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia [12].

Studies have expressed that human embryonic stem cell-derived epicardial cells intensify the heart regeneration process by the myocytes of the heart [11]. The epicardial cells reinforce coronary vessels and myocardium, and acts a source of trophic signals to maintain the heart during development and provides structural support for the adult heart. Research by Johannes Bargehr et al for the human embryonic stem cell derived epicardium’s ability to augument the structure and performance of engineered heart tissue internally showed that these epicardial cells remarkably enhance the ability to contract, myofibril structure and calcium handling of human engineered heart tissue, and also reduces passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells form constant fibroblast grafts in damaged hearts. Cotransplantation of epicardial cells derived from human embryonic stem cells and cardiomyocytes doubled the rate of proliferation of graft cardiomyocytes in vivo, resulting in 2.6-times greater cardiac graft size and concurrently augmenting graft and host vascularization. Notably, cotransplantation improved systolic performance compared with hearts receiving either only cardiomyocytes, only epicardial cells or vehicle [11]. The positive results of these tests on the rat models used go on to show the potential of epicardium derived from the human embryonic stem cells to enhance cardiac graft size and function, expressing their contribution to the formation of new myocardium and affirming them a promising adjuvant therapeutic for cardiac repair [11].

Mesenchymal stem cells (MSCS)

Mesenchymal stem cells are multipotent stromal cells that can differentiate into a range of varieties of cell types such as adipocytes, chondrocytes, osteoblasts. These cell types have been employed in the treatment of cardiovascular tissue damage and its potency in cardiac regeneration is still under immense research and exploration. Mesenchymal stem cells can be derived from various niches within the human organism, and thus there exists a hierarchical order of the regenerative potency of these cells with reference to their localization. The bone marrow has been identified as the source of quiet a great supply of mesenchymal stem cells in the body, but a number of sources have expressed the downsides of this population of cells to include reduction in ability to proliferate due to age. The extraction of these cells from bone marrow is also an invasive procedure, and this could cause infections and pain to the patients. Therefore mesenchymal stem cells from the such localizations as peripheral blood, pulmo, the cor and adipose tissue are preferentially explored for their biological properties, their expression of surface markers and their and the hierarchy of their capability to differentiate [13]

The mesenchymal stem cells utilize a mechanism that involves the activation of endogenous repair that includes the regulation of immune responses, inhibition of fibrosis, tissue perfusion, and rapid reproduction of resident cardiac cells [15].

According to the proposal of the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy, the minimal criteria to define human MSC are:

1. These stem cells must be plastic-adherent when under normal culture conditions.
2. Mesenchymal stem cells must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR surface molecules.
3. Mesenchymal stem cells must differentiate to osteoblasts, adipocytes and chondroblasts in vitro.

It is indicated however that these criteria will most likely require modification as new discoveries are made, and this limited set of standard criteria will promote a more uniform characterization of mesenchymal stem cells and facilitate the exchange of information among researchers [16].

Recycling Stem cells (RS cells) are the smallest groups, and divide the quickest. They are derived from bone marrow and are considered the most ancient and express a higher potential to differentiate into osteoblasts, chondrocytes and adipocytes under standard conditions [14]. Ian A. White et al in their review, further describe some features of different mesenchymal stem cells including:

Multipotent Adult Progenitor Cells (MAPCs) which are the sole mesenchymal stem cells that do not die in culture, they and the Human Bone marrow-derived Multipotent Stem Cells (hBMSCs) have the capability to differentiate into cells of all three germ layers.Cardiac Stromal Cells (CStCs) are a novel mesenchymal stem cell subgroup that arise from cardiac tissue. They express an elevated ability to show cardiovascular markers and differentiate into cardiomyocytes, and as well exhibiting a weakened ability to differentiate along the osteogenic and adipogenic lineages. Human Marrow-Isolated Adult Multilineage Inducible cells (MIAMI cells), which are not just multi-potent, but also express a good number of markers found among embryonic stem cells and pancreatic islet cells. Subgroups of c-kit (CD117) positive mesenchymal stem cells. some evidence suggests that these cells may make up a more homogeneous group of primitive mesenchymal stem cells expressing higher capacity for endodermal differentiation and hightened multilineage differentiation potency [14].

Conclusion.

After a critical review of various papers on numerous researches carried out to express the potency of various groups of stem cells that are being employed for therapeutic roles in the treatment of the various kinds of cardiovascular pathology, we have discovered that a substantial amount of these cells do in fact show potential for cardiac regeneration and improvement of cardiac tissue function post damage. Though there are many areas of concern surrounding the use of these methods in clinical practice, the effort and resources being invested in the research of these methods and to the perfection of this hypothesis are gradually dissolving the seemingly absurd nature of the possibility to regenerate cardiac tissue, and expressing the obvious possibilities that in a not so far future, we can have a sustainable and viable means of treating patients with different cardiovascular diseases and decrease death due to heart failure.