Besides cardiomyocytes (CM), the heart contains numerous interstitial cell types which play key roles in heart repair, regeneration and disease, including fibroblast, vascular and immune cells. However, a comprehensive understanding of this interactive cell community is lacking. We performed single-cell RNA-sequencing of the total non-CM fraction and enriched (Pdgfra-GFP+) fibroblast lineage cells from murine hearts at days 3 and 7 post-sham or myocardial infarction (MI) surgery. Clustering of >30,000 single cells identified >30 populations representing nine cell lineages, including a previously undescribed fibroblast lineage trajectory present in both sham and MI hearts leading to a uniquely activated cell state defined in part by a strong anti-WNT transcriptome signature. We also uncovered novel myofibroblast subtypes expressing either pro-fibrotic or anti-fibrotic signatures. Our data highlight non-linear dynamics in myeloid and fibroblast lineages after cardiac injury, and provide an entry point for deeper analysis of cardiac homeostasis, inflammation, fibrosis, repair and regeneration.

to clarify that statements made comparing this and previous studies relate to the published analyses of data within those studies and not the detection of genes within the datasets themselves. The changes made are shown below and both the online full-text and PDF versions have been updated. In the Introduction, the following statement was changed: Original However, existing datasets have apparently not provided the transcriptional depth to identify the signalling pathways that operate within the human fetal kidney, and fail to detect several known ligand and receptor expression patterns in mouse. Corrected The analyses performed on existing datasets have not comprehensively identified the signalling pathway components known to be operating within the mouse fetal kidney. In the Discussion, the following statements were changed: Original For example, although >20,000 cells were profiled at P1 (Adam et al., 2017), several known signalling molecules with functionally validated roles in the nephrogenic niche such as Gdnf, Fgf20, Fgf9, Bmp7, Wnt4 and Fgf8 were not detected in that analysis, precluding further insight into signalling interactions. Corrected Although >20,000 cells were profiled at P1 (Adam et al., 2017), several known signalling molecules with functionally validated roles in the nephrogenic niche were not highlighted in that analysis. Original The improved resolution of gene expression in our study may be due to sequencing depth (∼3000 genes detected per cell), biological replication and differential expression analysis with the edgeR method, which has recently been shown to be a top performer in a comparison of 36 differential expression analysis methods for scRNA-seq data (Soneson and Robinson, 2018). Corrected The improved analysis of signalling interactions provided in this study may be due to sequencing depth (∼3000 genes detected per cell), biological replication and differential expression analysis with the edgeR method, which has recently been shown to be a top performer in a comparison of 36 differential expression analysis methods for scRNA-seq data (Soneson and Robinson, 2018).

Chronic kidney disease is a progressive incurable pathology affecting millions of people. Intensive investigations aim to identify targets for therapy. We have previously demonstrated that abnormal expression of the Discoidin Domain Receptor 1 (DDR1) is a key factor of renal disease by promoting inflammation and fibrosis. The present study investigates whether blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology. Severe renal disease was induced by either injecting nephrotoxic serum (NTS) or performing unilateral ureteral obstruction in mice, and the expression of DDR1 was inhibited by administering antisense oligodeoxynucleotides either at 4 or 8 days after NTS (corresponding to early or more established phases of disease, respectively), or at day 2 after ligation. DDR1 antisense administration at day 4 stopped the increase of proteinuria and protected animals against the progression of glomeruloneprhitis, as evidenced by functional, structural and cellular indexes. Antisense administration at day 8 delayed progression –but to a smaller degree- of renal disease. Similar beneficial effects on renal structure and inflammation were observed with the antisense administration of DDR1 after ureteral ligation. Thus, targeting DDR1 can be a promising strategy in the treatment of chronic kidney disease.