Myofibroblasts represent a fascinating cell type in human biology, acting as an intermediate between the structural fibroblast and the contractile smooth muscle cell. These cells are transiently activated in response to tissue injury, possessing the dual capability of generating force and producing the structural components of tissue. They play a significant part in the body’s repair mechanisms, essentially serving as the cellular engine for wound closure. However, their continued presence beyond the needs of acute healing is directly linked to the development of chronic, debilitating diseases known as fibrosis.
Cellular Identity and Activation
Myofibroblasts are not typically found in healthy, quiescent tissue but emerge rapidly following an injury signal, representing an induced phenotype. The primary source for these cells is the differentiation of resident fibroblasts. Other cell types, such as pericytes surrounding blood vessels, also contribute to the myofibroblast population in certain organs, particularly in the kidney and lung. A less common pathway, epithelial-mesenchymal transition, where epithelial cells transform into a mesenchymal, fibroblast-like state, can also contribute to their numbers.
The defining characteristic of a myofibroblast is the expression of a specific protein, alpha-smooth muscle actin (\(\alpha\)-SMA), which is normally restricted to muscle cells. The incorporation of \(\alpha\)-SMA into the cellular cytoskeleton allows the myofibroblast to develop powerful, muscle-like contractile bundles, which are absent in a normal fibroblast. This acquisition of contractile machinery is a hallmark of the fully differentiated myofibroblast.
A molecule called Transforming Growth Factor-beta 1 (TGF-\(\beta\)1) is a potent inducer of this differentiation process. TGF-\(\beta\)1, along with mechanical tension from the surrounding damaged tissue, signals the fibroblast to upregulate \(\alpha\)-SMA expression and begin its specialized functions. Myofibroblasts are capable of both generating significant mechanical force and synthesizing large amounts of extracellular matrix proteins.
Essential Role in Normal Tissue Repair
The physiological function of the myofibroblast is directly related to its role in acute wound healing, where its presence is temporary and beneficial. When tissue is damaged, these cells quickly migrate into the injury site, forming what is known as granulation tissue. Their contractile machinery, powered by \(\alpha\)-SMA, allows them to actively pull the edges of the damaged tissue closer together, a process termed wound contraction. This action is important for minimizing the surface area of the wound, which significantly accelerates the closure process.
While contracting the wound, myofibroblasts also reconstruct the damaged area by producing and depositing extracellular matrix (ECM). This matrix, rich in components like collagen, provides the necessary scaffold to restore the structural integrity of the tissue. This temporary matrix eventually matures into a stable scar, which serves as a permanent patch for the injury. The entire process is tightly regulated to prevent excessive tissue remodeling.
Upon successful wound closure and the re-establishment of tissue continuity, the myofibroblasts are programmed to disappear. The vast majority of these cells undergo apoptosis. This self-destruction mechanism is necessary to prevent the continued contractile and matrix-producing activity of the cells. The removal of the myofibroblasts ensures that the tissue returns to a quiescent state, leaving behind a stable, non-progressive scar.
Pathological Persistence and Fibrosis
In certain chronic conditions, the normal resolution phase of wound healing fails, leading to the pathological persistence of myofibroblasts and the progressive accumulation of scar tissue known as fibrosis. Instead of undergoing apoptosis, the myofibroblasts remain active, continuously receiving signals from the microenvironment that promote their survival and function. This non-resolving state is often driven by sustained inflammation, mechanical strain, and high concentrations of growth factors like TGF-\(\beta\)1. The failure of the cells to deactivate is the defining feature that converts a temporary repair process into a chronic disease.
The persistent myofibroblasts produce and deposit excessive amounts of extracellular matrix components. This uncontrolled deposition leads to the progressive stiffening and hardening of the affected organ, a process that fundamentally alters the tissue architecture. The resulting stiff matrix creates a vicious cycle, as the increased mechanical tension itself further promotes the survival and activity of the myofibroblasts. This self-amplifying process gradually replaces functional tissue with non-functional scar.
The consequence of this pathological persistence is the progressive loss of organ function, as the dense scar tissue cannot perform the specialized tasks of the original organ cells. Fibrosis is a feature of numerous severe diseases across the body, where the myofibroblast is the primary effector cell. Examples include:
- Liver cirrhosis, where scar tissue replaces healthy liver cells.
- Idiopathic pulmonary fibrosis (IPF), where lung tissue becomes stiff and impairs breathing.
- Kidney fibrosis.
- Heart failure, often following chronic injury or hypertension.
Targeting the mechanisms that allow myofibroblasts to evade apoptosis and continue their matrix production is a focus of current medical research. Strategies aim to either induce the programmed cell death of the persistent cells or to inhibit their ability to synthesize collagen. By understanding how these cells transition from beneficial repair agents to destructive fibrotic drivers, researchers hope to develop new treatments that can halt or even reverse the progression of these devastating fibrotic diseases.