Agglomeration to nodules modulates human arterial smooth muscle cells to distinct postinjury phenotype via foam cell transition.

Cultures of arterial smooth muscle cells (SMCs) tend to form loci with multilayered growth as "hills" or "nodules," which is unusual for normal but common for transformed cells. Earlier it was shown that such nodules were composed of SMCs with the distinctive properties of small cell size, low adhesivity, and scarce or no fibronectin and filamentous actin, features which may also characterize tumor cells. Similar properties could be induced by cultivation of SMCs in aggregates, indicating modulation of SMCs to a distinct "multilayered" phenotype, rather than selection of variant SMCs with preference for multilayered growth. Transfer of SMCs to a three-dimensional arrangement by agglomeration to nodules, "spheroids," by seeding of SMCs on low-adhesive substratum, like agarose, was followed by signs of SMC injury with focal autodigestion and with loss of material from the cells, which to some extent was deposited extracellularly, transition to foam cells with cholesterol accumulation mainly as cholesteryl esters, and eventually decrease in cell size. Identically treated fibroblasts showed similar, but much less pronounced, changes and were largely protected by whole blood serum, in contrast to SMCs. The results indicate that the "multilayered" SMC type can be conceived of as a postinjury phenotypic state which is preceded by overt cellular injury and transition to foam cells in conjunction with sudden transfer to three-dimensional arrangement in spheroids. It is suggested that similar modulation may be important in atherosclerosis, in which foam cell transition and deposition of debris are prominent changes.