Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps

Abstract

In response to myocardial infarction (MI), the wound healing response of the left ventricle (LV) comprises overlapping inflammatory, proliferative, and maturation phases, and the cardiac fibroblast is a key cell type involved in each phase. It has recently been appreciated that, early post-MI, fibroblasts transform to a proinflammatory phenotype and secrete cytokines and chemokines as well as matrix metalloproteinases (MMPs). Later post-MI, fibroblasts are activated to anti-inflammatory and proreparative phenotypes and generate anti-inflammatory and proangiogenic factors and extracellular matrix (ECM) components that form the infarct scar. Additional studies are needed to systematically examine how fibroblast activation shifts over the timeframe of the MI response and how modulation at different activation stages could alter wound healing and LV remodeling in distinct ways. This review summarizes current fibroblast knowledge as the foundation for a discussion of existing knowledge gaps.

Keywords: big data; computational models; extracellular matrix; fibroblast; inflammation; myocardial infarction; omics.

Figure 1. Temporal fibroblast phenotypes post-myocardial infarction (MI)

We propose that cardiac fibroblasts (cFs) exhibit distinct phenotypes at different time points post-MI. At day (D) 0 (basal condition), resident fibroblasts synthesize extracellular matrix (ECM) to maintain homeostasis. At day 1 post-MI, fibroblasts exhibit a pro-inflammatory subtype, secreting pro-inflammatory mediators and matrix metalloproteinases. At day 3, fibroblasts produce anti-inflammatory and pro-angiogenic mediators to facilitate the formation of granulation tissue. At day 7, fibroblasts are pro-reparative, generating anti-inflammatory and pro-angiogenic mediators and synthesizing new ECM. At day 28, fibroblasts return to a homeostatic-like phenotype to maintain post-reparative homeostasis. The different colors of the cells depict differential fibroblast phenotypes at each time point post-MI.

Figure 2. Fibroblast signaling module

The signaling pathways begin at the extracellular-cell membrane interface, where cytokines, chemokines, growth factors, extracellular matrix (ECM) proteins, and mechanical signals act as inputs and transmit signals through cell surface receptors. While the exact signals operational post-MI have not been fully mapped, in vitro evidence indicates that these signals culminate in the release and activation of a wide variety of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), cytokines, and growth factors. This cascade leads to multiple effects on a variety of cell physiology variables to modulate all three phases of cardiac remodeling.