Platelet polyphosphate induces fibroblast chemotaxis and myofibroblast differentiation

Abstract

BackgroundPlatelets secrete many pro‐wound healing molecules such as growth factors and cytokines. We found that releasates from activated human platelets induced the differentiation of cultured murine and human fibroblasts into a myofibroblast phenotype. Surprisingly, most of this differentiation‐inducing activity was heat‐stable, suggesting it was not due to the protein component of the releasates. Inorganic polyphosphate is a major constituent of platelet‐dense granules and promotes blood coagulation and inflammation. ObjectivesWe aim to investigate the contribution of polyphosphate on myofibroblast differentiating activity of platelet releasates. MethodsUsing NIH‐3T3 cells and primary human fibroblasts, we examined the effect of human platelet releasates and chemically synthesized polyphosphate on fibroblast differentiation and migration. ResultsWe found that the myofibroblast‐inducing activity of platelet releasates was severely attenuated after incubation with a polyphosphate‐degrading enzyme, and that fibroblasts responded to platelet‐sized polyphosphate by increased levels of α‐smooth muscle actin, stress fibers, and collagen. Furthermore, fibroblasts were chemotactic toward polyphosphate. ConclusionsThese findings indicate that platelet‐derived polyphosphate acts as a cell signaling molecule by inducing murine and human fibroblasts to differentiate into myofibroblasts, a cell type known to drive both wound healing and fibrosing diseases. Polyphosphate therefore not only promotes early wound responses through enhancing fibrin clot formation, but also may play roles in the later stages of wound healing, and, potentially, progression of fibrotic diseases, by recruiting fibroblasts and inducing their differentiation into myofibroblasts.