Abstract
Variants of versican have wide-ranging effects on cell and tissue phenotype, impacting proliferation, adhesion, pericellular matrix composition, and elastogenesis. The G1 domain of versican, which contains two Link modules that bind to hyaluronan (HA), may be central to these effects. Recombinant human G1 (rhG1) with an N-terminal 8 amino acid histidine (His) tag, produced in Nicotiana benthamiana, was applied to cultures of dermal fibroblasts, and effects on proliferation and pericellular HA organization determined. rhG1 located to individual strands of cell surface HA which aggregated into structures resembling HA cables. On both individual and aggregated strands, the spacing of attached rhG1 was similar (~120 nm), suggesting interaction between rhG1 molecules. Endogenous V0/V1, present on HA between attached rhG1, did not prevent cable formation, while treatment with V0/V1 alone, which also bound to HA, did not induce cables. A single treatment with rhG1 suppressed cell proliferation for an extended period. Treating cells for 4 weeks with rhG1 resulted in condensed layers of elongated, differentiated α actin-positive fibroblasts, with rhG1 localized to cell surfaces, and a compact extracellular matrix including both collagen and elastin. These results demonstrate that the G1 domain of versican can regulate the organization of pericellular HA and affect phenotype.
Highlights
The domain structure of the gene and core protein of the extracellular matrix (ECM) proteoglycan versican, through alternative splicing of exons, gives rise to multiple isoforms of different sizes
We have investigated the effect of histidine (His)-tagged recombinant human G1, produced in the tobacco plant, on the phenotype of cultured human dermal fibroblasts
We report that the G1 domain of versican interacts with endogenously produced hyaluronan (HA) at periodic sites along the HA strand and promotes aggregation of HA strands into cable-like structures in the pericellular matrix (PCM) of the cultured cells
Summary
The domain structure of the gene and core protein of the extracellular matrix (ECM) proteoglycan versican, through alternative splicing of exons, gives rise to multiple isoforms of different sizes. The modular nature of the versican core protein creates a highly diverse molecular constituent of the ECM capable of binding to a variety of factors involved in ECM remodeling and regulation of cell phenotype. These variants have different effects on the ECM impacting such events as cell proliferation, cell adhesion and migration, pericellular coat formation, and Received for publication December 21, 2015; accepted March 17, 2016
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