The discovery that cells secrete extracellular vesicles (EVs), which carry a variety of regulatory proteins, nucleic acids, and lipids, has shed light on the sophisticated manner by which cells can communicate and accordingly function. The bioactivity of EVs is not only defined by their internal content, but also through their surface associated molecules, and the linked downstream signaling effects they elicit in target cells. The extracellular matrix (ECM) contains signaling and structural molecules that are central to tissue maintenance and repair. Recently, a subset of EVs residing within the extracellular matrix has been identified. Although some roles have been proposed for matrix-bound vesicles, their role as signaling molecules within the ECM is yet to be explored. Given the close association of EVs and the ECM, it is not surprising that EVs partly mediate repair and regeneration by modulating matrix deposition and degradation through their cellular targets. This review addresses unique EV features that allow them to interact with and navigate through the ECM, describes how their release and content is influenced by the ECM, and emphasizes the emerging role of stem-cell derived EVs in tissue repair and regeneration through their matrix-modulating properties.

Significance: Tropoelastin, the precursor molecule to elastic fibers, is a large, flexible elastic protein whose structure has been the subject of investigation and debate over several decades. Here, we present the fully atomistic structure of human tropoelastin, based on molecular dynamics simulations, and validate it with experiments. We explore the functional role of two key residues by inserting alanine substitutions and explain conformational changes and variations in hierarchical assembly. We also predict essential dynamics of the molecule by building elastin network models, to explain experimentally observed differences in assembly. Finally, we study the structural and dynamic molecular changes associated with the acquired cutis laxa disorder. The approach developed here is applicable for studying structure and function of other highly disordered proteins.

Significance: Extracellular matrix proteins have primarily been designated as supporting scaffolds for cells. This work presents the soluble extracellular matrix component tropoelastin as a powerful proproliferative and cell-attractive molecule that surpasses the potency of conventional growth factors and matrix proteins used in a mesenchymal stem cell (MSC) culture. Tropoelastin is also demonstrated to modulate MSCs both as a substrate coating and as a soluble additive in media, which significantly deviates from the classical dogma of cell anchorage-dependent structural roles of the matrix. We show that these activities of tropoelastin can be harnessed and establish a path to boosting the efficacy of and simplifying processes for clinical MSC expansion and therapeutic MSC recruitment.