Fibroblast contributions to ischemic cardiac remodeling

Abstract

The heart can respond to increased pathophysiological demand through alterations in tissue structure and function . This process, called cardiac remodeling, is particularly evident following myocardial infarction (MI), where the blockage of a coronary artery leads to widespread death of cardiac muscle. Following MI, necrotic tissue is replaced with extracellular matrix (ECM), and the remaining viable cardiomyocytes (CMs) undergo hypertrophic growth. ECM deposition and cardiac hypertrophy are thought to represent an adaptive response to increase structural integrity and prevent cardiac rupture. However, sustained ECM deposition leads to the formation of a fibrotic scar that impedes cardiac compliance and can induce lethal arrhythmias. Resident cardiac fibroblasts (CFs) are considered the primary source of ECM molecules such as collagens and fibronectin, particularly after becoming activated by pathologic signals. CFs contribute to multiple phases of post-MI heart repair and remodeling, including the initial response to CM death, immune cell (IC) recruitment, and fibrotic scar formation. The goal of this review is to describe how resident fibroblasts contribute to the healing and remodeling that occurs after MI, with an emphasis on how fibroblasts communicate with other cell types in the healing infarct scar ^–.

Keywords: Fibroblast; Fibrosis; Heart; Ischemia; Remodeling.

Figure 1:. Stress-induced cardiovascular changes.

Physiological stress via exercise causes global hypertrophy that does not impede cardiovascular function or result in fibrosis. In exercise models, CM length and width is increased proportionally by longitudinal hypertrophic growth. Pathological stress can induce concentric hypertrophy where myocyte width increases greater than myocyte length (PO) or can induce eccentric hypertrophy (dilation) where myocytes are stretched, and their length increases much greater than their width (MI or HF). Healthy or exercised hearts lack fibrosis, but in PO models, interstitial and perivascular fibrosis occur throughout the heart while in MI models, large areas of CM death are repaired by replacement fibrosis. MI, myocardial infarction; PO, pressure overload.

Figure 2:. Time-course of healing post-MI in mice.

Immediately following an occlusion of a coronary blood vessel, the Necrotic Phase occurs with downstream CM necrosis in response to lack of nutrients. Next, the Inflammatory Phase occurs with a surplus of invading ICs to clear cellular debris and promote pro-inflammatory signaling. During this phase, angiogenesis also begins. CFs begin to proliferate during the Reparative Phase, which also induces fibroblast activation and a shift from pro-inflammatory to pro-reparative IC interactions. Lastly, the Maturation Phase is identified by large amounts of ECM deposits, collagen cross-linking, and the transition of AFs to a matrifibrocyte state. AF, activated fibroblast; CF, cardiac fibroblast; CM, cardiomyocyte; EC, endothelial cell; ECM, extracellular matrix; IC, immune cell.

Figure 3:. Summary of CF interactions post-MI in mice.

Throughout the healing continuum post-MI, CFs interact with CMs, ECs, and ICs. In each phase of healing, different interactions become prominent that contribute to the microenvironment and signaling from CFs to other cardiac cells. During the necrotic and inflammatory phases, DAMPs that originate from dying CM signal the danger response to surrounding cells. Pro-inflammatory signaling is a major component of CFs and ICs interactions during the early phases of healing, and other pro-angiogenic and cell adhesion proteins are also secreted. During the proliferative and reparative phases, enriched gene expression programs include pro-resolution cytokines and matrix building molecules. Positive feedback from ECM tension and growth factors contributes to the progression of fibroblast activation and pathological fibrosis. Lastly, during the maturation phase, collagen cross-linking and modifying factors and chondrocyte factors are secreted from a specialized fibroblast called the matrifibrocyte. ANGPT1, angiopoietin 1; CCL5, C-C motif chemokine ligand 5; CM, cardiomyocyte; CHAD, chondroadherin; CLIP1, cartilage intermediate layer protein; COMP, cartilage oligomeric matrix protein; DAMPs, damage associated molecular patterns; EC, endothelial cell; ECM, extracellular matrix; FN, fibronectin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IC, immune cell; IFNγ, interferon gamma; IL, interleukin; LOX, lysyl oxidase; MFGE8, milk fat globule epidermal growth factor 8; MIF, macrophage migration inhibitory factor; MMPs, matrix metalloproteinases; POSTN, periostin; TGFβ−1, transforming growth factor β−1; TIMPs, tissue inhibitors of MMPs; TNFα, tumor necrosis factor α; TSP, thrombospondin; VEGF, vascular endothelial growth factor.