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Cell Biology
Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge.
- myofibroblast
- fibrosis
- wound healing
1. Myofibroblasts
In 1971, Gabbiani et al. identified large fibroblast-like cells within granulation tissue that had 40–80 A° diameter filamentous fibres traversing their entire cytoplasm. Since similar features are typical of smooth-muscle cells, the term ‘myofibroblast’ was coined (essentially, muscle-fibroblast intermediate cells) and it was proposed that these cells were implicated in wound contraction [1,2]. Further characterisation identified that the filamentous fibres were actin-based, with incorporated myosin and α-smooth muscle actin (α-SMA) proteins. Therefore, the myofibroblast’s ability to exert contractile force and to contract the wound edge was explained [3,4,5]. Myofibroblasts are morphologically enlarged and irregular (star or web-shaped) fusiform cells with well-developed cell–matrix focal interactions and intracellular gap junctions [6,7]. The incorporation of α-SMA into actin stress fibres grants the myofibroblast contractile power, approximately 2-fold that of the force of fibroblasts, when cultured on substrates with high elastomer stiffness [8,9,10]. Increased production of extracellular matrix (ECM) components: type I and type III fibrillar collagens, hyaluronan (HA), fibronectin (FN), and extra domain A fibronectin (EDA–FN) distinguish the hallmarks of myofibroblasts [11]. This elevated ECM content is not always causally linked, driving the myofibroblast differentiation process. Rather, there is a prominent interplay between ECM composition/arrangement and myofibroblast formation/function [12,13]. Following the delineation of the roles of myofibroblasts in wound contracture, they were quickly established as key drivers of progressive organ fibrosis [14], and have since been implicated in tumour development and metastasis [15,16]. More recently, studies describing an array of functions and regulatory factors exhibited by myofibroblasts have suggested roles beyond wound contraction and scar formation, including macrophage-like phagocytosis [17], immunomodulation [18,19], and autophagy [20].
2. Myofibroblast Origins
Multiple cell types are suggested to give rise to myofibroblasts, seemingly dependent on the tissue type. The heterogenous origins of myofibroblasts implies that these cells can form inside almost every tissue within the human body. In addition to resident fibroblasts and pericytes, their cellular origins include circulating bone-marrow-derived fibrocytes, tissue-derived mesenchymal stem cells, local epithelial and endothelial cells, de-differentiated smooth muscle cells, other hepatic stellate cells, mesangial cells, Schwann cells, and even monocytes and macrophages [21,22,23,24].
Differentiation from resident fibroblasts, present within most organs and connective tissues, is the best described process of myofibroblast development. Resting (inactivated) fibroblasts produce ECM and matrix proteases required for homeostatic turnover [25]. Upon activation, fibroblasts become highly migratory, proliferative, and increase the production of ECM, enzymes, and cytokines [26,27]; this transitional, activated state is termed the proto-myofibroblast. Despite limited information available in the literature regarding this phenotype, key features of the activated fibroblast, or proto-myofibroblast, have been described [28]. The rearrangement of the actin cytoskeleton from largely membrane-associated monomeric G-actin to polymerised cytoplasmic F-actin stress filaments, which traverse the length of the widened cell, is a hallmark feature [10]. These stress fibres allow junction formation with ECM components and other cells via integrin-containing complexes at the cell membrane and cadherin-type adherens junctions, respectively [7,29]. The absence of α-SMA within these stress fibres allows for proto-myofibroblast distinction from myofibroblasts [28]. Maturation into myofibroblasts can be determined by the neo-expression of α-SMA-positive stress fibres [30].
3. Myofibroblasts in Skin Fibrosis
The fibrotic process is characterised by chronic inflammation; altered epithelial–mesenchymal interactions; fibroblast proliferation, and fibroblast–myofibroblast differentiation. The latter feature (differentiation of fibroblasts into myofibroblasts) is central to the dysregulated and excessive production of collagen-rich ECM, otherwise called scar tissue. Myofibroblasts are thought to be terminally differentiated cells that typically undergo apoptosis [31,32,33,34] after wound contraction, as they are rarely found in non-pathological situations. Upon tissue trauma, myofibroblasts contribute to excessive ECM production for rapid, albeit dysfunctional, tissue repair. The tissue defect is repaired, but at the cost of function, as the organised spatial arrangement of specialised cells and ECM constituents is replaced by disorganised, abundant fibrous ECM. In this regard, the myofibroblast could be considered the primordial emergency repair cell. The aberrant persistence and chronic activation of myofibroblasts can lead to the development of pathological healing called fibrosis, which afflicts most tissues within the body. Progressive fibrosis leading to organ failure is considered the end-stage pathology of multiple diseases affecting the major organs, including but not limited to myocardial fibrosis [35], pulmonary fibrosis [36], liver cirrhosis [37], and chronic kidney disease [38]. Skin fibrosis (cicatrix) is an umbrella term for a large, heterogeneous spectrum of pathological conditions that affect the skin. Examples of skin conditions in which myofibroblast activity is central include hypertrophic and keloid scars, scleroderma, Dupuytren’s contracture, eosinophilic fasciitis, and chronic graft-versus-host disease [39,40,41,42,43,44]. The shared features of the abnormal and excessive accumulation of ECM constituents, particularly collagens, HA, and FN, in these diseases are governed by the myofibroblast phenotype. Infiltration of immune cells into fibrotic tissue also plays a key role in amplifying the fibrotic response, by secreting several cytokines and chemokines responsible for fibroblast–myofibroblast differentiation, the stimulation of ECM deposition, and the further recruitment of immune cells [45].
4. Future Perspectives for the Discovery of Novel Therapeutics
The complex multistage process of wound healing is vulnerable to dysregulation by a plethora of factors that can initiate and maintain myofibroblast differentiation. Failure of timely wound resolution and myofibroblast apoptosis can inevitably result in the excessive and disorganised deposition of the collagen-rich ECM that is characteristic of fibrosis. The growing knowledge base surrounding myofibroblast cell formation, function, and profibrotic regulators of differentiation has revealed promising candidate therapies that target the myofibroblast phenotype and functions at various stages of wound healing, with the aim to achieve attenuated scar formation. In the wake of unsatisfactory pre-clinical and clinical trial results from the inhibition of TGF-β1, researchers have sought alternative routes to preventing myofibroblast differentiation. Fibroblasts resistant to TGF-β1-stimulated myofibroblast differentiation, such as embryonic fibroblasts, oral mucosal fibroblasts, and aged/senescent fibroblasts, which continue to be extensively studied to uncover important targets, including cytokines, ECM components, receptors, and intracellular signalling cascades involved in resistance to myofibroblast phenotypic acquisition. Fundamental research into molecular-based interventions have given rise to an abundance of candidate treatment modalities, but a key limitation remains: namely a deficit of cell-specific targeted therapies due to the current lack of identified markers unique to myofibroblasts, perhaps as a result of their heterogenous origins. Biomaterials and drug carrier technologies may offer circumvention by facilitating the localised release of bioactive molecules within the microenvironment and the vicinity of myofibroblasts and are likely to take precedence in the sophisticated and controlled spatiotemporal delivery of therapeutic agents to wound sites. The progress and increased accessibility of single cell analytics and multi-omics may help to further identify subsets of dermal fibroblasts (e.g., fibroblasts from papillary or reticular dermis) or myofibroblasts that have more prominent roles in driving fibrosis, and this may facilitate the discovery of uniquely expressed cell surface receptors, proteins, or other targetable moieties. An alternative strategy only briefly touched upon here includes the regulation of cell–cell dynamics. Research into direct heterogenous cell binding, cell paracrine activity, and influence on surrounding cells may provide further clues towards myofibroblast regulation (e.g., leukocyte, stem cell, keratinocyte/epithelial cell, or endothelial cell regulation of fibroblasts and vice versa). Regardless of the afflicted tissue, the underlying cellular aetiology of fibrosis is largely similar. This undoubtedly implies that the progress of research in organ fibrosis will also provide applicable therapies for scarless wound healing.
This entry is adapted from the peer-reviewed paper 10.3390/biom11081095
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