Platelet polyphosphate induces fibroblast chemotaxis and myofibroblast differentiation

Abstract

Background: Platelets 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. Objectives: We aim to investigate the contribution of polyphosphate on myofibroblast differentiating activity of platelet releasates. Methods: Using NIH-3T3 cells and primary human fibroblasts, we examined the effect of human platelet releasates and chemically synthesized polyphosphate on fibroblast differentiation and migration. Results: We 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. Conclusions: These 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.

Fibrin with Laminin-Nidogen Reduces Fibrosis and Improves Soft Palate Regeneration Following Palatal Injury

“…This may be due to the lack of other components of the normal blood clot such as platelets. In vitro, platelet-derived polyphosphates induce the differentiation of fibroblasts from skin into myofibroblasts [43]. Moreover, platelets contain large amounts of TGF-β1, a key factor in fibrosis and scarring.…”

Update on platelet procoagulant mechanisms in health and in bleeding disorders

“…After release, the larger size platelet polyP molecules bind to the platelet surface and assemble into nanoparticles that enhance factor XII activation 21 . Platelet polyP is also postulated to have additional effects on fibroblasts and myofibroblasts that enhance wound healing 31 …”

“…21 Platelet polyP is also postulated to have additional effects on fibroblasts and myofibroblasts that enhance wound healing. 31…”

Platelet functional responses and signalling: the molecular relationship. Part 1: responses.

“…They contain mostly low-molecular-weight compounds, the major of them being ADP able to activate other platelets [39]. Another component that has been recently attracting a lot of attention is polyphosphate reported to have a number of potential roles in the coagulation cascade [40,41]. The functional role of other dense granule components such is ATP, serotonin, calcium is much less clear [41,42].…”

“…Another component that has been recently attracting a lot of attention is polyphosphate reported to have a number of potential roles in the coagulation cascade [40,41]. The functional role of other dense granule components such is ATP, serotonin, calcium is much less clear [41,42]. In contrast to integrin activation, dense granule release is not easily mediated by all activators; for example, ADP itself causes it only to a very minor degree [43].…”