Excerpt
Over the past 17 years, cardiosphere-derived cells (CDCs) have been developed as a therapeutic candidate for regenerative therapy [
23,
30]. These cardiac stromal cells (which are entirely distinct from discredited c-kit-positive cells [
7,
36]) exhibit multilineage potential and clonogenicity [
10,
30], thus qualifying as progenitors, but work primarily through indirect mechanisms [
9,
14]. At least 70 independent labs worldwide have published on CDCs (see, e.g. [
1,
11,
27,
31,
32,
39]). Meanwhile, ten clinical trials, seven in the USA and three independently performed in Japan, have investigated CDCs for cell therapy. The first, an NIH-funded trial called CADUCEUS [
19,
21], used intracoronary autologous CDCs in patients with mild heart failure with reduced ejection fraction (HFrEF) following myocardial infarction (MI). The Japanese trials have likewise used autologous CDCs, with a focus on hypoplastic left ventricle (LV) or dilated cardiomyopathy [
31]. Subsequent clinical trials in the USA have used allogeneic CDCs, which were found to produce equivalent benefits but are more realistic as clinical products [
20,
23]. These include ALLSTAR [
18] (post-MI patients with mild HFrEF; NCT01458405), DYNAMIC [
6] (advanced HFrEF; NCT02293603), and HOPE-Duchenne [
33] and HOPE-2 [
25] (for muscular dystrophy and its associated cardiomyopathy; NCT02485938 and NCT03406780). Those trials, now completed, have verified not only are CDCs safe, but also they may have disease-modifying bioactivity in humans. Mechanistically, the prevailing concept of CDC efficacy centers on the “paracrine hypothesis”, which posits transplanted cells produce salutary soluble factors [
13]. Benefits of CDCs and their secreted paracrine factors include anti-fibrotic effects [
34,
35], anti-apoptotic effects on myocytes [
8,
16], angiogenesis [
9,
34], modulation of inflammatory processes and oxidative stress [
3,
34], and promotion of cardiomyocyte cell cycle re-entry [
22]. CDC-secreted exosomes, CDC
EXO (which are a class of extracellular vesicles), mediate the major benefits of CDCs via cell–cell transfer of therapeutic payloads [
2,
14,
29]. Analysis of CDC
EXO payload using RNA sequencing (RNA seq) and proteomics has revealed numerous species of noncoding RNA (ncRNA) and proteins [
5,
14], some of which are known to be bioactive and others which have yet to be functionally characterized. …
