Cardiac fibroblasts are crucial to heart functioning and remodeling. In addition to providing structural support, they also respond to electrical, chemical, and mechanical stimuli. Their role in pathological disorders such as myocardial infarction, heart failure, and hypertension has prompted considerable research on these cells.
Cardiac Fibroblasts
Fibroblasts are cells that synthesize and secrete proteins that form an extracellular matrix (ECM), such as collagen, fibronectin, laminin, etc., providing the structural support for cells to grow. Therefore, they are located in the connective tissue. Cardiac fibroblasts constitute 50% of the cellular composition of the heart.
Cardiac Fibroblast Structure
One characteristic feature of fibroblasts is the lack of basement membrane, unlike other cells of the heart. The cardiac fibroblast structure is flat-spindle-shaped with cytoplasmic extensions. They contain prominent Golgi apparatus and rough endoplasmic reticulum. Since their morphology and activity vary with their location, studies have attempted to find a definitive marker of cardiac fibroblasts that can distinguish them from other heart cells, such as cardiomyocytes, endothelial cells, and vascular smooth muscle cells. Recent studies have suggested discoidin domain receptor 2 (DDR2) and fibroblast-specific protein-1 (FSP1) as the fibroblast-specific markers. Vimentin, fibronectin, connexin, periostin, integrin, etc., are also some of the highly expressed genes of cardiac fibroblasts.
Cardiac Fibroblast Functions
Cardiac fibroblasts generated ECM maintain the structural integrity of the heart. Additionally, they perform the following functions to contribute to tissue functioning.
- They synthesize and degrade ECM which forms a three-dimensional network for other cardiac cells to interact. The ECM distributes the mechanical forces on the heart and also relay mechanical signals between cells via cell-ECM adhesion molecules.
- These cells can also sense mechanical, chemical, and electrical changes, gaining them the name of sentinels. They connect to ECM via cadherins and connexins, allowing rapid detection of signals. In response to the mechanical stimuli, they can modulate the ECM production and degradation for adequate functioning of the heart.
- Research has also indicated that cardiac fibroblasts secrete molecules that modify the structure and function of cardiomyocytes and contribute to their growth, proliferation, and maturation.
- These cells connect to cardiomyocytes via connexins, allowing fibroblasts to synchronize and relay electrical activity within the tissue. It stands to reason that fibroblast bridges the isolated cardiomyocytes to maintain electrical physiology of the heart. The electrical coupling between the both can modify the action potential and contraction in the heart.
- During the development stage of the heart, fibroblasts release chemokines, cytokines, and growth factors to assist the process. They self-replicate to maintain tissue homeostasis and drive connective tissue remodeling for cardiogenic reprogramming.
- During injury, fibroblasts transform into myofibroblasts that form fibrotic scar tissue and prevent the rupture of the myocardium.
Communication between Cardiac Fibroblasts and Cardiomyocytes
The electric coupling between fibroblasts and cardiomyocytes defines the electric conduction and contraction of cardiac tissue. The research suggests that the density of fibroblasts affects the conduction velocity. The coupling can occur in the following different approaches:
Gap Junctions: Gap junctions form channels between cells for direct transfer of molecules. Connexins such as Cx43, Cx45, and Cx40 form the gap junctions in a homomeric or heteromeric manner. Age and cardiac injury show abnormalities in the expression and distribution of the connexins.
Membrane Nanotubes: These nanotubes connect the cells over long distances. They are transient in nature and consist of membrane-bound connections composed of F-actin or microtubules. He et al. demonstrated that fibroblasts communicate via the tubes to cardiomyocytes and exchange calcium ions. They offer the advantage over gap junctions, facilitating long-distance connectivity and transporting large molecular weight entities like organelles and vesicles.
Paracrine Signaling: Several studies have cocultured fibroblasts with cardiomyocytes under physical separation or cultured cardiomyocytes in fibroblast conditioned media to identify more methods of communication between the cells. The studies demonstrated that fibroblast conditioned media reduced cardiomyocyte contraction. In fact, the conditioned media obtained from myocardial infarct models shortened the duration of action potential in comparison to normal fibroblast conditioned media.
All these mechanisms are still under investigation to gain understanding about the communication pathways and utilize them for therapeutic purposes.
Cardiac Fibrosis
Although fibroblasts maintain the connective tissue, their improper activation can lead to overproduction of ECM, causing cardiac fibrosis. Fibrosis impart stiffness to the cardiac tissue impeding the contraction and electrical conduction activities.
The Role of Cardiac Fibroblasts: Heart injury such as ischemia or blood pressure, promotes the migration of fibroblasts and immune cells to the injury site. The endothelial and immune cells around the injury activate the fibroblasts to undergo conversion into myofibroblasts.
Myofibroblasts: Fibroblasts alter their characteristics, gaining the expression of α-smooth muscle actin (α-SMA) that confer contractile properties and are termed myofibroblasts. They also possess highly active endoplasmic reticulum and ruffled membrane. These cells secrete ECM proteins as well as matrix-degrading proteases and proteinase inhibitors for remodeling or fibrosis. Myofibroblasts release pro-fibrotic factors like transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF). If the injury causes necrosis of cardiomyocytes, which ECM then replaces, it is referred to as replacement fibrosis. Interstitial fibrosis describes the ECM deposition in the absence of cardiomyocyte loss.
TGFβ Signaling Pathways: The TGFβ signaling is the key pathway regulating the differentiation into myofibroblasts. Factors like angiotensin II, toll-like receptors, oxidative stress, inflammatory cytokines, etc., stimulate the expression of TGFβ. TGFβ binds to type II receptors that phosphorylate type I receptors and follow canonical or noncanonical mechanisms. Canonical pathways include the recruitment of SMAD proteins at the logan-receptor complex and their activation. Activated SMAD proteins transport to the nucleus and act on the coactivator to trigger the gene expression required for myofibroblasts. In noncanonical pathways, TGFβ acts via PI3K/Akt pathways. TGFβ is also associated with Wnt signaling pathways, and according to studies, GSK-3β mediates this association.
Ongoing Research
The research and understanding of cardiac fibroblasts is limited. Due to their involvement in cardiovascular disease, they are currently under investigation. Researchers employ cardiac fibroblast cell lines like immortalized human cardiac fibroblasts (IM-HCF) or 3T3 cell lines belonging to mouse embryonic fibroblasts. However, primary cells are still preferred for their physiological relevance.
- Fibroblasts are heterogeneous cells, showing different features during the multi-step conversion to myofibroblasts. The distinctive marker is still required to identify the different subpopulations of these cells. It can provide insights into the tissue-specific role of these cells in cardiac functioning.
- The origins of myofibroblasts are unclear and many precursors have been suggested. Due to the role of myofibroblasts in cardiac fibrosis, identifying the cells responsible for forming myofibroblasts and the process is crucial.
- Cardiac fibrosis is a complex involving diverse signaling pathways. It causes severe cardiovascular disorders, urging deep exploration of these pathways for the development of therapeutic intervention.
The Key Takeaways
Cardiovascular diseases have been on the rise in recent years. They are the key mediators of cardiac fibrosis that lead to critical cardiac disorders. With the rising number of deaths due to cardiac dysfunction, the research on these cells has notably surged. Kosheeka provides these cells from diverse species to assist in your research. Their team evaluates the cardiac fibroblasts thoroughly and guarantees the purity, viability, and sterility of cells to enhance your research.
FAQs
Q: What are cardiac fibroblasts?
These are heart cells that synthesize the extracellular matrix. The matrix supports the structure of the heart, facilitates cell-cell interaction, and relay signals to cells.
Q: What causes cardiac fibrosis?
Injury drives the migration of fibroblasts to the site for healing. The cells and cytokines initiate a signaling cascade that differentiates them into myofibroblasts resulting in a fibrotic tissue.
Q: What are the characteristics of myofibroblasts?
Myofibroblasts show distinctive expressions of α-smooth muscle actin, collagen, and periostin. They overproduce extracellular matrix and have contractile properties.
Q: Which cells produce myofibroblasts?
The precursors of myofibroblasts are still under investigation. However, fibroblasts, hematopoietic cells, and endothelial cells have been suggested to form myofibroblasts.
