ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation

Abstract

SUMMARYFocal adhesions anchor cells to extracellular matrix (ECM) and direct assembly of a pre-stressed actin cytoskeleton. They act as a cellular sensor and regulator, linking ECM to the nucleus. Here, we identify proteolytic turnover of the anti-adhesive proteoglycan versican as a requirement for maintenance of smooth muscle cell (SMC) focal adhesions. Using conditional deletion in mice, we show that ADAMTS9, a secreted metalloprotease, is required for myometrial activation during late gestation and for parturition. Through knockdown of ADAMTS9 in uterine SMC, and manipulation of pericellular versican via knockdown or proteolysis, we demonstrate that regulated pericellular matrix dynamics is essential for focal adhesion maintenance. By influencing focal adhesion formation, pericellular versican acts upstream of cytoskeletal assembly and SMC differentiation. Thus, pericellular versican proteolysis by ADAMTS9 balances pro- and anti-adhesive forces to maintain an SMC phenotype, providing a concrete example of the dynamic reciprocity of cells and their ECM.

The “other” 15–40%: The Role of Non‐Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon

“…104 The properties of the PCM can be modulated by the activity of cell-surfaceassociated proteases or by altering the gene expression of PCM components in response to physiological and pathological stimuli. 105,106 Recently, proteomics studies identified more than 100 proteins at the cell surface and the PCM of tenocytes, illuminating the complexity of this ECM compartment. 103,107 Some of these PCM components, for which functions have been established, are discussed below.…”

The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ hematoendothelial progenitors

“…Versican and HA form a pericellular matrix in fibroblasts and vascular and myometrial smooth muscle cells (Evanko et al, 1999;Hattori et al, 2011;Mead et al, 2018) which is influential in determining cell phenotype. Specifically, HA, which is extruded from HAS2 complexes in the cell membrane, is decorated with versican and the complex is retained at the cell surface by binding CD44, HAS2 and other receptors (Evanko et al, 2007).…”

“…The versican-HA pericellular matrix has a well-established impact on different cells. It is anti-adhesive (Evanko et al, 1999;Mead et al, 2018), which may allow the Flk1+ cells to migrate and proliferate efficiently after their emergence at gastrulation. Another possible role of versican-HA is sequestration of vasculogenic factors such as VEGF-A.…”

“…Proteoglycans, which are composite ECM and cell-surface molecules with one or more glycosaminoglycan chains covalently attached to a core protein, participate in all these mechanisms. For example, chondroitin sulfate proteoglycans (CSPGs) such as versican, which are bulky and inherently anti-adhesive, regulate focal adhesion formation and inhibit cell migration (Mead et al, 2018;Perris et al, 1996;Yamagata et al, 1989). Heparan sulfate proteoglycans (HSPGs) sequester growth factors, including angiogenic growth factors such as VEGF-A and FGF2 through heparan sulfate (HS) chains and act as co receptors for angiogenic signaling (van Wijk and van Kuppevelt, 2014).…”

“…Its C-terminal G3 domain binds to ECM components fibronectin, fibrillins and tenascins (Wu et al, 2005) as well as VEGF-A (Zheng et al, 2004). Through interaction of HA with cell-surface receptors such as CD44, versican is a major component of pericellular matrix, where it regulates cell adhesion and consequently, contractile cytoskeleton assembly, and is postulated to influence cell differentiation through this mechanism (Hattori et al, 2011;Mead et al, 2018;Nandadasa et al, 2015). Four versican isoforms (V0, V1-V3) arise from alternative splicing of large exons, numbered 7 and 8, that encode the CS-bearing domains, named GAGα and GAGβ respectively (Dours-Zimmermann and Zimmermann, 1994;Shinomura et al, 1993).…”