"The role of stem cells in myocardial regeneration"

Abstract

Looking back at the techniques concerning cell types that have been used for myocardial regeneration, six are the main categories of cells that appear to be able to improve the myocardial composition (SKMS, BMNCs, MSCs, CSCs/CDCs, CD133+ /CD34+ , ESCs/iPSCs), as well as their combination. Most of them achieve this by partial fusion into the myocardial tissue of the recipient or through paracrine effects in which the endogenous cardiac stem cell population of the heart is activate, but in ESCs / iPSCs and CSCs / CDCs we also have differentiation of transferred cells into mature cardiomyocytes. All categories lead to a reduction in infarcted tissue, fibrous tissue and its collagen content while creating new, functional myocardial tissue, and through angiogenesis to increase of local perfusion and at the same time the conversion of immobile or akinetic tissue into dyskinetic or even the restoration of its mobility. Thickening of the anterior wall of the left ventricle increases, the elasticity of the myocardium increases, as does its systolic function, and hypertrophy, leading to an increase in cell size, is inhibited. In most cases these structural changes translate into functional improvement (increase in ejection fraction or length of enddiastolic diameter at the end of contraction-fractional shortening) or reduction in left ventricular size (end-diastolic volume, end-systolic volume) other than CD133+ /CD34+ . Apoptosis is inhibited, cardioprotection is possible and patients' lives recover qualitatively. Unfortunately, this does not mean that we have perfected these techniques, that trying to regenerate myocardium with stem cells is a panacea at itself, or that clinical practice has become routine.

In fact, when the transplants of these cells began, the expectations were much higher than the outcome proved out to be. Many times, the results of the studies included the creation of ectopic tissues (although in general the transport of cells is safe 106 with appropriate measures), or adverse effects of cells after some time with various clinical forms such as recurrence of myocardial infarction, arrhythmias, ventricular tachycardia, respiratory or circulatory problems, need to return to hospital or even death often attributed to cell transport. One of the most notable and interesting of these problems, arrhythmias, have been associated with increased heart size and decreased heart rate and are found mainly in cell types such as SKMS and ESCs / iPSCs. At the same time, especially in the last decade, an attempt has been made to transfer cells embedded in biomaterialsscaffolds,such as cell sheets, hydrogels, 2D constructions or the omental flap in order to address inherent problems of cell transfer or the cells themselves, such as the interaction with their environment, mechanical stress, apoptosis and cell death factors of their transport environment, their inability to integrate with host tissues and their long-term survival, as well as insufficient myocardial perfusion. These problems were logical given the pioneering ideas, the multitude of signaling pathways and molecules that exist in the myocardial tissue, and the so far limited clinical practice.

Skepticism and thorough criticism are in demand, especially with the ethical issues that have been raised about the handling of cells such as ESCs, despite their contribution to basic research and regenerative medicine. In the future, there are many issues that await clarification or refinement in this field. First, what are the cell categories that could be combined for the best synergistic effect and what are the appropriate dosages to use. Next, which is the best way to transfer the cells to the myocardial environment, so as not to cause further injuries to the myocardium and to be integrated-divided, but also in what time after the infarct episode must the cells be transplanted (multiple transfers over time?). Then, the transferred cells could be combined with mild drugs to help them integrate, interact, or perhaps prolong their survival in the myocardial environment. It is necessary to identify a global model with the appropriate myocardial environment that will support the tests so that there is no multitude of contradictory results in the evolutionary range of animal models but also a more objective statistical tool that will detect changes in the myocardial environment and give value on the enhancing effects of transplanted cells. In the century of bioinformatics, the classification and differentiation of candidate cells according to the molecular markers they carry and which are expected to affect the functional state of the recipient's heart, has already begun, while during the transplants risk factors attributed to donor cells but also in the receiver, such as age, smoking and others are taken into consideration. Finally, new genomic identity management tools, such as CRISPR-Cas9, enable better donor-recipient matching at the genomic level and give new strength, especially to cells of allogeneic origin, which help to avoid time, effort and risk in transplants, in order to avoid and immunological and inflammatory reactions.

PAPANIKOLAOU Dimitrios