Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease

Abstract

Fibroblasts comprise the largest cell population in the myocardium. In heart disease, the number of fibroblasts is increased either by replication of the resident myocardial fibroblasts, migration and transformation of circulating bone marrow cells, or by transformation of endothelial/epithelial cells into fibroblasts and myofibroblasts. The primary function of fibroblasts is to produce structural proteins that comprise the extracellular matrix (ECM). This can be a constructive process; however, hyperactivity of cardiac fibroblasts can result in excess production and deposition of ECM proteins in the myocardium, known as fibrosis, with adverse effects on cardiac structure and function. In addition to being the primary source of ECM proteins, fibroblasts produce a number of cytokines, peptides, and enzymes among which matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), directly impact the ECM turnover and homeostasis. Function of fibroblasts can also in turn be regulated by MMPs and TIMPs. In this review article, we will focus on the function of cardiac fibroblasts in the context of ECM formation, homeostasis and remodeling in the heart. We will discuss the origins and multiple roles of cardiac fibroblasts in myocardial remodeling in different types of heart disease in patients and in animal models. We will further provide an overview of what we have learned from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs and TIMPs.

Figure 1

Origin of cardiac fibroblasts during development and disease. During development, epicardium-derived cells undergo epithelial–mesenchymal transformation (EMT), while endothelial cells (from the endocardium) can undergo endothelial–mesenchymal (EndMT) and transform to cardiac fibroblasts. Following myocardial injury, bone marrow (BM)-derived cells (monocytes, BM progenitors and fibrocytes) can be recruited to the site of injury and transformed to cardiac fibroblasts. This can occur in addition to EMT and/or EndMT.

Figure 2

Pluripotent cardiac fibroblasts impact different aspects of cardiac structure and function. Cardiac fibroblasts can produce a number of active peptides (for example, cytokines, growth factors, peptides), extracellular matrix (ECM) proteins (collagens, elastin, fibronectin, and so forth), and ECM-regulatory proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). As such, cardiac fibroblasts can impact molecular and cellular events that collectively determine cardiac structure and function.

Figure 3

Structure of collagen molecule. Pro-collagen is comprised of two alpha-1 chains and one alpha-2 chain intertwined into a triple helix. Pro-peptide domains at the carboxy-terminals and amino-terminals are cleaved, resulting in formation of mature collagen. When collagen is degraded, during physiological turnover or pathological adverse remodeling, telopeptides (from the amino-terminals or carboxy-terminals) are cleaved and released into the plasma.