Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs’ cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.

从人类心脏活组织检查中产生的心球衍生细胞 (CDC) 已在临床试验中显示出具有改善疾病的生物活性。矛盾的是，CDC 在心脏中的细胞起源仍然难以捉摸。我们使用单细胞 RNA 测序 (sc-RNAseq) 研究了 CDC 与心脏非肌细胞和非造血细胞（心脏成纤维细胞/CF、平滑肌细胞/SMC 和内皮细胞/EC）的分子特性。我们将 CDC 鉴定为一种独特且富含线粒体的细胞类型，它与非肌细胞具有生物学相似性，但与源自人类诱导的多能干细胞的心脏祖细胞没有相似性。CXCL6成为 CDC 的新特异性标记物。通过分析来自人类右心房活检的 sc-RNAseq 数据并与 CDC 进行比较，我们发现了 CDC 和 CF 之间的转录组学相似性。通过直接比较婴儿和成人 CDC sc-RNAseq 数据，婴儿 CDC 揭示了与心脏发育相关的 GO 术语。为了分析 CDC 的有益作用（促血管生成、抗纤维化、抗细胞凋亡），我们对 CDC 衍生的细胞外囊泡 (EV) 进行了功能性体外测定。CDC EVs 增强了体外血管生成，但不刺激疤痕形成。他们还减少了促凋亡Bax的表达在新农合中。总之，CDC 被披露为富含线粒体的细胞，具有独特的特性，但也与右心房 CF 有相似之处。CDC 显示出高度增殖、分泌和免疫调节特性，这些特性也可以在活化或炎症细胞类型中找到。通过特殊的培养条件，CDCs 获得了一些生物活性，包括血管生成潜力，这可能会改变某些疾病的疾病。