Cardiac Fibroblast Diversity

Abstract

Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.

Keywords: adventitia; fibroblast; inflammation; interstitium; myocardial infarction; myofibroblast.

Figure 1

Anatomic location of cardiac fibroblasts. Fibroblasts reside in distinct anatomic locations in the heart, and each population of fibroblasts is likely to express a different transcriptional profile. ➊1 Atrium-transverse section of atria where cardiomyocyte fibers are thinner and less dense compared to the ventricles. The fibroblast to cardiomyocyte ratios in atria have not been clearly documented. ➋2 Adventitia-transverse section through a coronary artery. The number of vascular smooth muscle cells (VSMCs) can vary depending on vessel diameter. Cell types other than fibroblasts have also been noted in the dense collagen surrounding the vessel. ➌3 The annulus fibrosus is a collagen-rich area surrounding the conduction system. Fibroblasts are present in these regions. ➍4 Valves: Fibroblasts reside in three layers (fibrosa, spongiosa, and ventricularis). These are composed of collagen, proteoglycans, and elastin, respectively. ➎5 Interstitium: This longitudinal section of myocardium would be found in the ventricles or ventricular septum.

Figure 2

Fibroblast stages at rest and after injury. Several studies have found three subsets of resting cardiac fibroblasts. After injury or infection or during aging, fibroblasts become activated in response to inflammatory cytokines or cardiomyocyte-secreted factors. Fibroblasts enter a proliferative phase, which may overlap with the production of extracellular matrix (ECM). The expanded population of fibroblasts can be divided into at least four different subsets. Myofibroblasts are α-SMA⁺, while α-SMA⁻ cells may promote angiogenesis. There are multiple proposed fates for the expanded fibroblasts. Some revert to resting fibroblasts, whereas others exhibit a unique and continued ECM production phase. Others either undergo apoptosis or become senescent. Although multiple studies have implicated a role for fibroblasts in regulating inflammation, single-cell sequencing experiments have not described an inflammatory gene expression profile. Below each fibroblast phase are some markers that may be expressed by a majority of cells in that phase.