Thrombin‐activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin‐like growth factor‐1

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Platelet components have found successful clinical utilization to initiate or to accelerate tissue‐repair mechanisms. However, the molecular pathways by which platelet factors contribute to tissue regeneration have not been fully elucidated. We have studied the effect of thrombin‐activated platelets (TAPs) on cell growth in vivo and in cultured cell systems. Application of TAPs to ulcerative skin lesions of diabetic patients induced local activation of ERK1/2 and Akt/ PKB. Moreover, when applied to cultured human skin fibroblasts, TAPs promoted cell growth and DNA synthesis and activated platelet‐derived growth factor (PDGF) and insulin‐like growth factor (IGF)‐1 receptor tyrosine kinases. PDGF was released by TAPs and rapidly achieved a plateau. At variance, the release of IGF‐1 was mainly provided by the TAPs‐stimulated fibroblasts and progressively increased up to 48 h. The PDGF‐R blocker Ag1296 reduced the activation of Akt/PKB and, at a lesser extent, of ERK1/2. Conversely, inhibition of IGF‐1 signaling by Ag1024 and expression of a dominant‐negative IGF‐1R mutant selectively reduced the stimulation of ERK1/2 by TAPs and fibroblast‐released factors, with minor changes of Akt/PKB activity. Thus, platelet factors promote fibroblast growth by acutely activating Akt/PKB and ERK1/2. Sustained activation of ERK1/2, however, requires autocrine production of IGF‐1 by TAPs‐stimulated fibroblasts.—Giacco, F., Perruolo, G., D'Agostino, E., Fratellanza, G., Perna, E., Misso, S., Saldalamacchia, G., Oriente, F., Fiory, F., Miele, C., Formisano, S., Beguinot, F., Formisano, P. Thrombin‐activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin‐like growth factor‐1. FASEB J. 20, E1763–E1772 (2006)

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