Single-cell transcriptomics of cardiac progenitors reveals functional subpopulations and their cooperative crosstalk in
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Protein & Cell
LETTER
Dear Editor, Myocardial infarction is one of the leading causes of morbidity and mortality. Stem/progenitor cells therapy has emerged as a promising strategy for the cardiac repair, especially those derived from cardiac tissue, have attracted worldwide attention (Tompkins et al., 2018). However, challenges and controversies remain in characterizing functional progenitors and explaining their mechanisms of action. Cardiosphere-derived cells (CDCs) are the only type of cardiac progenitor that has been demonstrated to be reparative for multiple heart diseases in both laboratory researches and clinical trials (Cambier et al., 2017; Sano et al., 2018). CDCs are generated based on their sphere formation capability without extra marker-based purification. Dissecting the heterogeneity of CDCs may provide novel insights into the potential relationship between their cellular composition and function, which is thereby important for clarifying current controversies over cardiac progenitors, and developing better therapies. CDCs were isolated and characterized as reported (Figs. 1A and S1) (Cambier et al., 2017; Sano et al., 2018; Zhao et al., 2018). Using single-cell RNA sequencing (scRNA-seq), a total of 11,376 cells were profiled in an unbiased manner, and 9,621 cells were eventually analyzed after rigorous quality control (Fig. S2). As a result, 6 distinct clusters consisting of as few as 25 cells to as many as 6,054 cells per cluster were identified (Fig. 1B). Cluster-specific differentially expressed genes (DEGs) and their top GO terms were generated (Figs. 1C and S3). The potential identity of these clusters was proposed via calculating the correlation score with known cell types (Fig. S4) (Sun et al., 2019); the smallest cluster #5 was identified as endotheliallike cells, while all others are mesenchymal/stromal/fibroblast-like cells (Fig. S4). Interestingly, we found that the Ly6a gene (encoding stem cells antigen-1, Sca-1) was particularly expressed in some clusters, and could divide CDCs into two major subpopulations: Sca-1+ CDCs (cluster #0, cluster #2, and cluster #4) and Sca-1− CDCs (cluster #1 and cluster #3)
© The Author(s) 2020
(Figs. 1D and S5A). Flow cytometry confirmed these two distinct groups, with the ratio of Sca-1+ cells in CDCs at 30% approximately (Fig. S5B and S5C). CDCs originated from mesenchymal/fibroblast cells in the heart (Fig. S4) (Cambier et al., 2017), while Sca-1 has long been considered as a stromal progenitor marker. To reveal the cellular origin of Sca-1+ CDC, we analyzed a published dataset of cardiac cells at various stages (Fig. S6) (DeLaughter et al., 2016), and found the proportion of Sca-1+ cells was increased in these mesenchymal stromal cells/fibroblast-enriched cells (MSCs/FCs) during perinatal and postnatal cardiac development (Fig. S7A–D). Specifically, a marked increase in the ratio of Sca-1+ CDCs-specific genes was observed in the cluster #1 of MSCs/FCs that is composed of mostly perinatal and postnatal cells, from which Sca-1+ CDCs may be largely originated (
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