# Cell Therapy in the Treatment of Coronary Heart Disease
## 5 Mechanisms of Action for Cardiac Cell Therapy  
The study of the mechanisms by which different types of transplanted cells regulate the regeneration of ischemic heart tissue is crucial for the advancement and improvement of cell therapy methods, and it is essential that these mechanisms be explored for a deeper understanding of the potential utility of cell therapy in the treatment of CHD. Both direct integration into the myocardium to compensate for cardiomyocyte or endothelial cell loss and indirect paracrine mechanisms may be involved in the ability to repair damaged tissue [23,134]. Direct cell or tissue replacement provides the most straightforward approach to remuscalarize the myocardium and restore function after acute infarction. For irreversible fibrosis or remodeling associated with chronic injury, a much larger and more complex indication than acute or subacute MI, remuscalarization may be the only  
Figure 2: Generating subtype-specific cardiomyocytes: Pluripot stem cells are induced to cardiac mesoderm through activation of Wnt and BMP signaling. Administration of Wnt inhibitors leads to the commitment of cardiac progenitors. RA signaling guides cardiac progenitors towards atrial subtype commitment, while inhibition of RA signaling promotes ventricular lineage differentiation. Furthermore, RA and BMP act together to induce cardiac progenitor cells to become nodal-like pacemaker cells. Wnt signaling additionally promotes the specification of pacemaker cells from cardiac mesoderm cells. BMP—bone morphogenetic protein, RA—retinoic acid. effective approach. However, at this stage of development, replacement therapies are still elusive and exploratory [21]. As evidenced by numerous in vitro and in vivo studies, paracrine signaling is the fundamental mechanism mediating the beneficial effects of cell therapy [83; 135]. Through paracrine signaling, transplanted cells are able to activate various signaling pathways and influence the surrounding cardiac tissue, independent of the establishment of functional intercellular contacts with the recipient cells [136]. Biologically active molecules including TGFb, VEGF, SDF1, EGF, and HGF can be secreted into the intercellular space or bloodstream by transplanted cells [137; 138]. Consequently, the release of cytokines or extracellular vesicles is a systemic event that stimulates various regenerative processes, such as neovascularization, reduced apoptosis of endogenous cardiomyocytes, activation of tissue progenitor cells, or recruitment of cells responsible for repair of damaged tissues [136; 139]. The secretome characteristics of transplanted cells and their ability to regenerate myocardium are strongly influenced by the health status and age of the donor, as well as the methods used to obtain and prepare the cellular material prior to transplantation [23]. Neovascular plays a critical role in regenerative processes by providing ischemically damaged tissue with the necessary nutrients and oxygen for replenishment, a process that is essential for tissue recovery. In a study using a mouse model of MI, researchers found that human CDCs released pro-angiogenic factors such as VEGF, HGF, and IGF1 after transplantation, and noted a 20% increase in neovascularization in the peri-infarct region following subcutaneous cell injection, which was mainly related to paracrine signaling [87]. A recent study confirmed the stimulatory effect of CDCs on angiogenesis in mice and identified endoglin (CD105) as an important mediator of this paracrine-induced neovascularization [140]. It was also shown that transplantation of rat c-Kit+ cardiac cells into the peri-infarct area significantly enhanced angiogenesis by secreting VEGF [141]. MSCs derived from different sources have the ability to release proangiogenic factors, which aids in the development of new blood vessels [136; 142]. In a study by [PERSON] et al., adipose tissue-derived MSCs were found to produce VEGF, HGF, and IGF1 in vitro and to increase capillary density in the peri-infarct area after transplantation into rats [143].