Suess Patrick M, Smith Stephanie A, Morrissey James H
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
J Thromb Haemost. 2020 Nov;18(11):3043-3052. doi: 10.1111/jth.15066. Epub 2020 Sep 10.
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.
We aim to investigate the contribution of polyphosphate on myofibroblast differentiating activity of platelet releasates.
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.
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.
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.
血小板分泌许多促进伤口愈合的分子，如生长因子和细胞因子。我们发现，活化的人血小板释放物可诱导培养的小鼠和人成纤维细胞分化为肌成纤维细胞表型。令人惊讶的是，这种诱导分化的活性大部分是热稳定的，这表明它不是由释放物中的蛋白质成分引起的。无机多聚磷酸盐是血小板致密颗粒的主要成分，可促进血液凝固和炎症反应。
我们旨在研究多聚磷酸盐对血小板释放物的肌成纤维细胞分化活性的作用。
使用NIH-3T3细胞和原代人成纤维细胞，我们检测了人血小板释放物和化学合成的多聚磷酸盐对成纤维细胞分化和迁移的影响。
我们发现，血小板释放物的肌成纤维细胞诱导活性在用多聚磷酸盐降解酶孵育后严重减弱，并且成纤维细胞对血小板大小的多聚磷酸盐的反应是α-平滑肌肌动蛋白、应力纤维和胶原蛋白水平增加。此外，成纤维细胞对多聚磷酸盐具有趋化性。
这些发现表明，血小板衍生的多聚磷酸盐通过诱导小鼠和人成纤维细胞分化为肌成纤维细胞而作为一种细胞信号分子，肌成纤维细胞是一种已知可驱动伤口愈合和纤维化疾病的细胞类型。因此，多聚磷酸盐不仅通过增强纤维蛋白凝块形成促进早期伤口反应，而且还可能在伤口愈合的后期以及潜在的纤维化疾病进展中发挥作用，通过募集成纤维细胞并诱导它们分化为肌成纤维细胞。
