Matricellular homologs in the foreign body response: hevin suppresses inflammation, but hevin and SPARC together diminish angiogenesis.

Implanted foreign materials, used to restore or assist tissue function, elicit an initial acute inflammatory response followed by chronic fibrosis that leads to the entrapment of the biomaterial in a thick, poorly vascularized collagenous capsule. Matricellular proteins, secreted macromolecules that interact with extracellular matrix proteins but do not in themselves serve structural roles, have been identified as important mediators of the foreign body response that includes inflammation, angiogenesis, and collagen synthesis and assembly. In this report we delineate functions of hevin and SPARC, two homologs of the SPARC family of matricellular proteins, in the foreign body response. Despite their sequence similarity, hevin and SPARC mediate different aspects of this fibrotic response. Using mice with targeted gene deletions, we show that hevin is central to the progression of biomaterial-induced inflammation whereas SPARC regulates the formation of the collagenous capsule. Although vascular density within the capsule is unaltered in the absence of either protein, SPARC-hevin double-null capsules show substantially increased numbers of vessels, indicating compensatory functions for these two proteins in the inhibition of angiogenesis. These results provide important information for further development of implant technology.

SPARC and tumor growth: where the seed meets the soil?

Matricellular proteins mediate interactions between cells and their extracellular environment. This functional protein family includes several structurally unrelated members, such as SPARC, thrombospondin 1, tenascin C, and osteopontin, as well as some homologs of these proteins, such as thrombospondin 2 and tensascin X. SPARC, a prototypic matricellular protein, and its homolog hevin, have deadhesive effects on cultured cells and have been characterized as antiproliferative factors in some cellular contexts. Both proteins are produced at high levels in many types of cancers, especially by cells associated with tumor stroma and vasculature. In this Prospect article we summarize evidence for SPARC and hevin in the regulation of tumor cell growth, differentiation, and metastasis, and we propose that matricellular proteins such as these perform critical functions in desmoplastic responses of tumors that culminate in their dissemination and eventual colonization of other sites.

Expression and characterization of murine hevin (SC1), a member of the SPARC family of matricellular proteins.

Hevin, also known as SC1, MAST 9, SPARC-like 1, RAGS1 and ECM2, is a member of the SPARC-related family of matricellular proteins. Mouse hevin is 53% identical to mouse SPARC, and both proteins share a follistatin-like module and an extracellular Ca(2+)-binding (E-C) domain. SPARC functions as a modulator of cell-matrix interactions, a regulator of growth factor activity, a de-adhesive protein, and a cell cycle inhibitor. Although the functions of mouse hevin are unknown, its human orthologue has been shown to be de-adhesive for endothelial cells. We now report the production of recombinant mouse hevin in insect cells through the use of a baculoviral expression system and its purification by anion-exchange, size-exclusion chromatography, and isoelectric focusing. Furthermore, we have produced rat anti-hevin monoclonal antibodies (MAbs) that have been characterized by indirect and capture ELISAs, immunoblotting, immunoprecipitation, and immunohistochemistry (IHC). Recombinant hevin, present as a soluble factor or bound to tissue-culture plastic, inhibited the spreading of bovine aortic endothelial cells in vitro. IHC analysis of hevin in normal human and mouse tissues revealed a limited expression pattern in many tissues, with particularly dominant staining in dermis, ducts, vasculature, muscle, and brain. In lung and pancreatic tumor xenografts, we found distinct reactivity with MAbs that were selective for stromal cells, tumor cells, and/or endothelial cells. Although similar to SPARC in its anti-adhesive activities, hevin nevertheless exhibits a distinctive histological distribution that, in certain invasive tumors, is associated with desmoplasia.