The cellular mechanisms driving cardiac tissue formation remain poorly understood, largely due to the structural and functional complexity of the heart. It is unclear whether newly generated myocytes originate from cardiac stem/progenitor cells or from pre-existing cardiomyocytes that re-enter the cell cycle. Here, we identify the source of new cardiomyocytes during mouse development and after injury. Our findings suggest that cardiac progenitors maintain proliferative potential and are the main source of cardiomyocytes during development; however, the onset of αMHC expression leads to reduced cycling capacity. Single-cell RNA sequencing reveals a proliferative, “progenitor-like” population abundant in early embryonic stages that decreases to minimal levels postnatally. Furthermore, cardiac injury by ligation of the left anterior descending artery was found to activate cardiomyocyte proliferation in neonatal but not adult mice. Our data suggest that clonal dominance of differentiating progenitors mediates cardiac development, while a distinct subpopulation of cardiomyocytes may have the potential for limited proliferation during late embryonic development and shortly after birth.

Cardiovascular disease is a leading cause of mortality in the world and is exacerbated by the presence of cardiac fibrosis, defined by the accumulation of non-contractile extracellular matrix proteins. Cardiac fibrosis is directly linked to cardiac dysfunction and increased risk of arrhythmia. Despite its prevalence, there is a lack of efficacious therapies for inhibiting or reversing cardiac fibrosis, largely due to the complexity of the cell types and signaling pathways involved. Ongoing research has aimed to understand the mechanisms of cardiac fibrosis and develop new therapies for treating scar formation. Major approaches include preventing the formation of scar tissue and replacing fibrous tissue with functional cardiomyocytes. While targeting the renin-angiotensinaldosterone system is currently used as the standard line of therapy for heart failure, there has been increased interest in inhibiting the transforming growth factor-β signaling pathway due its established role in cardiac fibrosis. Significant advances in cell transplantation therapy and biomaterials engineering have also demonstrated potential in regenerating the myocardium. Novel techniques, such as cellular direct reprogramming, and molecular targets, such as non-coding RNAs and epigenetic modifiers, are uncovering novel therapeutic options targeting fibrosis. This review provides an overview of current approaches and discuss future directions for treating cardiac fibrosis.

This study highlights the importance of genetic variation in cardiac fibrosis by using multiple inbred mouse strains to characterize CFbs and their response to ISO treatment. Our data suggest that, although fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In addition, by comparing CFbs from multiple strains, we identified pathways as potential therapeutic targets and LTBP2 as a marker for fibrosis, with relevance to patients with underlying myocardial fibrosis.

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Pdi1 knockdown decreases apoB100 synthesis, reduces MTP activity and apoB100 lipidation, and impairs the oxidative folding of apoB100, which causes defective VLDL secretion. PDI1 promotes formation of disulfide bonds in apoB100 and serves as its disulfide isomerase.

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Nkx2-5 is a homeobox-containing transcriptional regulator that serves as one of the earliest markers of cardiac lineage commitment. To study the role of Nkx2-5-expressing progenitors at specific time points in cardiac development, we have generated a novel and inducible NKX2-5 mouse line by knocking in a CreER cassette into the Nkx2-5 genomic locus, while preserving the endogenous Nkx2-5 gene to avoid haplo-insufficiency. We evaluated the specificity and efficiency of CreER activity after 4-OHT injection by crossing Nkx2-5CreER/+mice with a Rosa26tdT/+ reporter strain. Our immunohistochemistry results confirmed Cre-induced tdTomato expression specifically in cells expressing Nkx2-5. These cells were mainly cardiomyocytes and were observed in the embryonic heart as early as day 9.5. Additionally, quantitative PCR on postnatal hearts showed enriched expression of Nkx2-5 in isolated tdTomato-expressing cells. No tdTomato expression was observed in Nkx2-5CreER/+;Rosa26tdT/+ mice in the absence of 4-OHT, confirming the inducible nature of CreER activity. The Nkx2-5/CreER mouse model described in this paper will serve as an invaluable tool to trace myocardial lineage and to temporally induce genetic manipulation in a selective population of cardiac progenitors during embryonic development and in the adult heart.