Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C

Abstract

ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.

Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?

“…Moreover, the pentraxin-related protein 3 (PTX3) and the insulin-like growth factor binding protein 3 (IGFBP3) are both involved in cell proliferation/migration, inflammatory response, and ECM remodeling [51,52], as well as the matricellular protein transforming growth factor beta induced (TGFBI) that binds different ECM components (e.g., FN, COLLs) and participates in cell-ECM interactions through an ανβ3 integrin-mediated mechanism [53]. Interestingly, many of the dysregulated proteins in the hEDS secretome are predicted to be in EVs, which act as modulators of intercellular communications due to their ability to carry a broad range of bioactive molecules, including ECM components, matrix-modifying enzymes, and different RNA species [54]. Therefore, a possible contribution of EVs in the molecular mechanisms underlying disease pathogenesis seems plausible.…”

The Functional Role of Extracellular Matrix Proteins in Cancer

“…Fibronectin is also a cargo in extracellular vesicles (EV) from different cell types (reviewed in [ 197 ]). EV is a term used to define lipid bilayer membrane particles secreted by cells [ 198 ].…”

“…Like fibronectin, tenascin-C was also detected in extracellular vesicles released into the extracellular space by most cell types, including fibroblasts and tumor cells (reviewed in [ 197 ]). Moreover, tenascin-C was detected in exosomes isolated from the blood of glioblastoma patients [ 268 ].…”

Mechanical Compression of Human Airway Epithelial Cells Induces Release of Extracellular Vesicles Containing Tenascin C

“…EVs play a key role in cell-to-cell communication by transporting various cellular cargo from the donor cells to the recipient cells [ 44 , 45 , 59 , 69 , 70 ]. Thus, EVs were explored as a mechanism of exporting various biological components from the cells to the extracellular environment [ 43 ]. Extracellular TNC was detected in EVs released from various cancer cell types [ 43 , 71 ] Clinically, EVs containing TNC were detected in the plasma of patients with cancer [ 43 , 72 , 73 ].…”

“…While abundant TNC protein is detected in the asthmatic airway, little is known about the source of extracellular TNC or the mechanisms of TNC secretion and its subsequent deposition in the extracellular environment of the airway. In non-epithelial cells, one of the increasingly investigated mechanisms of extracellular TNC secretion is through extracellular vesicles (EVs) [ 43 ]. EVs are membrane-bound particles that play a role in intercellular communication by shuttling biological material between cells [ 44 , 45 , 46 ].…”