Mesenchymal stem cell in treatment for Ischemic heart disease
Ischemic heart disease (IHD), a life-threatening cardiac condition characterized by lessened blood and oxygen supply to the heart, which is the principal component of cardiovascular diseases (CVD), may lead to heart failure and myocardial infarction (MI) [1]. It is the major cause of death in urbanized nations and contributes significantly to the disease burden in developing nations [2].
Heart failure is prevalent, particularly in industrialized countries; it affects between 3% and 5% of the population and has developed into a growing disease with high diagnostic costs [3]. Despite tremendous progress in conventional treatment for ischemic heart disease, it still continues to be a major cause of death and disability.
Cell-based therapeutics hold an exciting frontier of research for complete cardiac recuperation [4]. They have analyzed the capacity of diverse stem and progenitor cells to stimulate cardiac renewal, with promising results in both pre-clinical and clinical trials. Researchers have found that mesenchymal stem cells (MSC) possess regenerative ability through various mechanisms, including differentiation from the mesoderm lineage, immunomodulatory properties, and paracrine effects. Also, their availability, maintenance, and ability to replenish endogenous stem cell niches have rendered them suitable for treating heart disease. [4]
Ischemic heart disease characteristics
Ischemic heart disease refers to heart weakening caused by reduced blood flow to the heart. Typically, this reduced blood flow results from coronary artery disease, a condition that occurs when your coronary arteries narrow. For cardiac viability and optimal function, equity between myocardial oxygen quantity and demand is required [5]. Myocardial ischemia occurs when mitochondria fail to supply the energy demand because of deficient oxygen supply when the myocardium shifts to anaerobic glycolysis to generate energy [6]. Because of anaerobic conditions, the myocardium has a limited ability to produce sufficient oxygen to sustain cardiomyocyte processes. Oxygen deprivation results in decreased nutrient availability and insufficient removal of metabolic end products. This process changes the series of events in cardiomyocyte’ biology and cardiac structure that occurs in endothelial cells, fibroblasts, vascular smooth muscle cells, and leukocytes [4]. It is the major reason for ischemic conditions and also for ischemic heart failure.
As your heart weakens, it has to work harder to send blood to the rest of your body. This can increase your risk of blood clots, heart valve disease, heart failure, abnormal heart rhythms (arrhythmia) and other problems [6].
Current therapies include inhibition of the angiotensin-altering enzyme, beta and aldosterone barriers, and biventricular striding [7]. However, mortality and morbidity [8] cause these strategies to succeed only temporarily, causing novel strategies to inhibit and reverse cardiac dysfunction.
Mesenchymal stem cell in treatment for Ischemic heart disease
In the 1990s, cell-based therapy gained popularity and researchers began promoting it as a promising field in regenerative medicine for repairing cardiac damage after MI [9]. Mesenchymal stem cells (MSCs) have occurred as a breakthrough treatment to “regrow” lost cardiomyocyte and repair endogenous tissue by paracrine signaling and exhibit novel immunomodulatory properties [10].
The clinical use of MSC started between 1995 and 2000, especially in treating cancer and bone/cartilage disease [11]. Later, the outcome of several clinical works adjudged the therapeutic potential and safety of using MSC in the treatment of acute myocardial ischemia (AMI) [12].
[4] Several kinds of research have contributed to the salutary effects of MSC therapy by various factors, both in vivo and in vitro, after cardiomyocyte. Feasible mechanisms consist of 1) new engraftment and differentiation into new cardiomyocyte or other cells; 2) paracrine signaling/mediators from MSC show adverse effects on cardiac repair; 3) MSC stimulates endogenous cardiac stem cells (CSC) to proliferate and repair injured tissues; as well as stimulation of neovascularization and immunomodulation. [4]
To prevent this, the demonstration of MSCs injected into the frontier region of infarcts and applicable cardiac tissue in pre-clinical and clinical trial settings [4]. It resulted in an anti-fibrotic effect, reducing scar size, promoting endogenous tissue regeneration, reduced inflammation, stimulating cellular growth, proliferation, and improving perfused and viable blood vessels to reverse the cardiac injury. The enhanced endogenous mechanism shows improved contractile cardiac muscle than the direct differentiation and engraftment of MSCs [13].
Interleukin-1 (IL-1) and -6 (IL-6) for angiogenesis promotion and VEGF induction, hepatocyte growth factor (HGF) for cardiac progenitor cell mobilization, transforming growth factor (TGF-) 1 acts as a fibrosis regulator, and placental growth factor (PLGF) and vascular endothelial growth factor (VEGF) work to prevent cardiomyocyte and endothelial cell death [14]. Angiogenin secretion is thought to function as LV remodeling attenuation via vasculogenesis [4]. A novel up-regulated secreted protein, Akt-MSC, induced hypoxic conditions to promote cardiomyocyte survival with reduced infarct size and reduced apoptosis [10].
In the myocardium, the secretion of paracrine factors has a pleiotropic effect, such as improvement in local angiogenesis, reduced cardiomyocyte death, low fibroblast activation, cardiac stem cell stimulation, and also a reduction in myocardial fibrosis, corresponding with the cell-mediated immune response [15]. Various preclinical research models have shown the secretion of soluble factors by the MSCs in different models.
Nakanishi and coworkers reported that the up-regulated expression of cardiac progenitor genes, namely myosin heavy chain and atrial natriuretic peptide (ANP), in a conditioned medium derived from MSCs. This paracrine activation enhanced the migration and differentiation of cardiac progenitor cells (CPC) [16].
In 2001, an developing study revealed that BM-derived cells from the murine model infused intramyocardial improved cardiovascular function after myocardial infarction (MI) (48%). After that, in 2004, Chen et al. (2004) demonstrated the intracoronary infusion method in autologous BM-derived MSCs improved the left ventricular (LV) function [4]. The key property of MSCs is that they lack major histocompatibility complex II (MHC-II) markers, they elude rejection by the immune system (both innate and adoptive) [17].
In randomized clinical trials, the trans-endocardial injection of both allogeneic and autologous derived MSCs in ischemic patients resulted in a favorable response in immunological reactions, the eminence of life, and ventricular remodeling [18]. A few scientists studied patients with heart failure caused by severe ischemic conditions in randomized, placebo-controlled trials. After a six-month study, MSC-treated patients revealed a substantial decline in LV and systolic volume and an increase in LV ejection infarction [4]. The success of these efficient studies made cardiac regeneration by cell-based therapy via mesenchymal stem cells more appealing in the research field.
Hare and his co-workers published the results of the POSEIDON randomized trial [19]. Thirty patients were enrolled with LV dysfunction because of ischemic cardiomyopathy (ICM). The researchers transferred a couple of autologous and allogeneic BM-MSC with a mean of 150 million cells via transendocardial injection. Both types of cells had similar effects at 13 months of follow-up, such as a reduced EED (infarct size) mean of about 33.21%.
In the PROMETHUS [20] trial, the researchers injected autologous BM via intramyocardial injection into kinetic myocardial territories of six people with chronic ischemic cardiomyopathy leading to CABG (cardiac artery bypass grafting). After 18 months, patients who received MSCs had a higher LV ejection fraction (+9.4± 1.7 percent, P = 0.0002) and a lower scar mass (–47.5 ±8.1 percent, P < 0.0001) than those who received placebo control. They also found that there was a coherent limitation in scar size, perfusion, and enhancement in contractility [4].
Researchers consider mesenchymal stem cells to have one of the best outcomes for ischemic heart disease and have showed their effectiveness in treating various cardiovascular diseases [21]. However, therapy using MSCs still faces many controversies and lacks safety for clinical application. Researchers and clinicians still need to conduct more in-depth research and clinical evaluation before they can use it as a treatment in the future.
References:
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