Self‐organization and pattern formation in calcifying vascular stem cells

Abstract

We previously observed patterns of evenly spaced stripes of calcified cellular aggregates in cultures of calcifying vascular cells (CVC), bovine smooth muscle cells purified by dilutional cloning. We hypothesized that the patterns were formed by a reaction‐diffusion process driven by interaction of a known morphogen, bone morphogenetic protein‐2 (BMP‐2), with its inhibitor, matrix GLA protein (MGP). We used mathematical models based on the biochemical and physical properties of BMP‐2 (autocatalytic, chemoattractant, and osteogenic) and MGP (inhibitory of BMP‐2 and rapidly diffusing).Computer simulations based on the math models predicted 2 experimental findings. Over 10–14 days, CVC cultures treated with exogenous MGP produced evenly spaced spots (nodules) rather than stripes, and CVC treated with warfarin (an inhibitor of MGP) produced stripes at double the density of untreated cultures. In addition, the models predicted conversion of diffuse cell density to focal nodules. In vivo, when CVC were implanted for 8 wks in subcutaneous diffusion chambers in hyperlipidemic mice, they produced tissue nodules resembling calcified atherosclerotic plaque.Thus, calcified atherosclerotic lesions may arise from cellular aggregates formed by reaction‐diffusion processes. Harnessing this mechanism may ultimately allow clinical control of focal vs. diffuse vascular disease.