# Cell Therapy in the Treatment of Coronary Heart Disease
## 3 Cardiac Origin Cells for Cardiac Cell Therapy
### Cardiosphere-Derived Cells  
The term \"cardiosphere\" was introduced in 2004 to describe undifferentiated cells obtained with enzymatic treatment of atrium wall explants [70]. Cardiospheres are a heterogeneous cell population comprised of a core of c-Kit+ cells, several layers of cells expressing connexin 43 (the primary gap junction protein in the heart), and an outer layer consisting of CD105-expressing cells on the surface [71; 72].  
Despite significant and increasing interest in this particular cell type, there remains limited understanding of their origin. It is believed that cardiospheres arise from stromal cells present in the myocardium and proliferate during primary culture to form cardiospheres in vitro [73].  
Research on the use of cardiosphere-derived cells (CDCs) for the treatment of experimental MI in rodents has demonstrated a relative improvement in the functional characteristics of the heart [70]. Studies comparing the efficacy of treating experimental MI in mice using bone marrow MSCs, adipose tissue MSCs, HSCs, and CDCs revealed that the group that underwent CDCs transplantation demonstrated the most significant recovery of cardiac muscle [74]. The authors attributed this advantage to the optimal conditions for transplanted cell functioningin the myocardium created by intercellular interactions within the cardiosphere. Meanwhile, intramyocardial transplantation of CDCs failed to demonstrate a therapeutic effect in several animal studies with artificially induced MI [75; 76].  
In 2007, a clinical protocol was established for extracting human cardiosphere cells through endomyocardial biopsy [71]. Experiments modeling ischemia-reperfusion in pigs have demonstrated the therapeutic potential of human CDCs [77]. The first phase of the CADUCEUS clinical trial investigated the intracoronary administration of autologous CDCs to post-MI patients [78]. The authors obtained myocardial slices from endocardial biopsy and subsequently isolated cardiospheres. The cardiospheres were administered to patients 2 to 4 weeks after MI, and the intervention was found to be safe for use in humans. The magnetic resonance imaging results after 3 months indicated that patients who underwent treatment experienced a decrease in the area of cardiosclerosis and an increase in healthy myocardial mass and left ventricular wall thickness. However, there were no significant differences in ejection fraction observed [78]. Subsequent clinical trials in the United States employed allogeneic CDCs, revealing comparable therapeutic results, and greater potential for use as a cell product for treating CHD [73]. These trials encompassed ALLSTAR (mild heart failure and low ejection fraction in post-MI patients) [79], DYNAMIC (severe heart failure and low ejection fraction in post-MI patients) [80], HOPE-Duchenne, and HOPE-2 (patients with Duchenne muscular dystrophy and cardiomyopathy) [81; 82]. The completed studies confirmed the safety of using CDCs in clinical settings and demonstrated their potential for disease-modifying biological activity [73].  
The CDCs' efficiency is mainly based on the \"paracrine hypothesis\". This suggests that the transplanted cells produce vesicles that contain biologically active molecules [73; 83], leading to therapeutic effects such as antifbiotic [84], antiapoptotic [85; 86], angiogenesis stimulation [87; 88], modulation of inflammatory processes, and oxidative stress control [88; 89], as well as cardiomyocytes re-entering the cell cycle stimulation [90].