Abstract
Cardiac fibrosis is a common pathological change associated with cardiac injuries and diseases. Even though the accumulation of collagens and other extracellular matrix (ECM) proteins may have some protective effects in certain situations, prolonged fibrosis usually negatively affects cardiac function and often leads to deleterious consequences. While the development of cardiac fibrosis involves several cell types, the major source of ECM proteins is cardiac fibroblast. The high plasticity of cardiac fibroblasts enables them to quickly change their behaviors in response to injury and transition between several differentiation states. However, the study of cardiac fibroblasts in vivo was very difficult due to the lack of specific research tools. The development of cardiac fibroblast lineage-tracing mouse lines has greatly promoted cardiac fibrosis research. In this article, we review the recent cardiac fibroblast lineage-tracing studies exploring the origin of cardiac fibroblasts and their complicated roles in cardiac fibrosis, and briefly discuss the translational potential of basic cardiac fibroblast researches.
Highlights
Cardiac fibrosis is commonly associated with cardiovascular diseases (CVDs), the leading cause of death in western countries
Studies utilizing Tcf21 (Tcf21-MerCreMer), Wt1 (Wt1-Cre), and Tbx18 (Tbx18-Cre) cis-regulatory elements-controlled lineage-tracing mouse lines have shown that epicardial progenitors give rise to both cardiac fibroblasts and vascular smooth muscle cells developmentally (Cai et al, 2008; Zhou et al, 2008; Smith et al, 2011; Acharya et al, 2012; Moore-Morris et al, 2014), which is consistent with earlier experiments conducted using chick embryos (Mikawa and Gourdie, 1996)
Being the most abundant cell type in the heart, it is undoubted that the cardiac fibroblast is an excellent target for treating cardiac diseases
Summary
Cardiac fibrosis is commonly associated with cardiovascular diseases (CVDs), the leading cause of death in western countries. Studies utilizing Tcf (Tcf21-MerCreMer), Wt1 (Wt1-Cre), and Tbx (Tbx18-Cre) cis-regulatory elements-controlled lineage-tracing mouse lines have shown that epicardial progenitors give rise to both cardiac fibroblasts and vascular smooth muscle cells developmentally (Cai et al, 2008; Zhou et al, 2008; Smith et al, 2011; Acharya et al, 2012; Moore-Morris et al, 2014), which is consistent with earlier experiments conducted using chick embryos (Mikawa and Gourdie, 1996) In mice, these epicardial cardiac fibroblast progenitors express PDGFRα and start the epithelial-to-mesenchymal transition (EMT) around embryonic day 14.5 (E14.5). This requires the understanding of the functions of genes expressed in cardiac fibroblasts and their roles in disease development These studies have been greatly promoted by CreloxP-mediated cardiac fibroblast lineage-tracing mouse lines, which allows specific knockout and overexpression of genes in cardiac fibroblasts in vivo without affecting other tissues/cell types (see Table 1 for a summary of recent relevant studies). Temporary improved of function (Smad deletion); exacerbated long-term function and enchanced ECM maladaptive remodeling (Smad deletion)
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