Abbonante Vittorio, Di Buduo Christian Andrea, Gruppi Cristian, De Maria Carmelo, Spedden Elise, De Acutis Aurora, Staii Cristian, Raspanti Mario, Vozzi Giovanni, Kaplan David L, Moccia Francesco, Ravid Katya, Balduini Alessandra
Department of Molecular Medicine, University of Pavia, Italy.
Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
Haematologica. 2017 Jul;102(7):1150-1160. doi: 10.3324/haematol.2016.161562. Epub 2017 Apr 14.
Megakaryocytes (MK) in the bone marrow (BM) are immersed in a network of extracellular matrix components that regulates platelet release into the circulation. Combining biological and bioengineering approaches, we found that the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4), a mechano-sensitive ion channel, is induced upon MK adhesion on softer matrices. This response promoted platelet production by triggering a cascade of events that lead to calcium influx, β1 integrin activation and internalization, and Akt phosphorylation, responses not found on stiffer matrices. Lysyl oxidase (LOX) is a physiological modulator of BM matrix stiffness collagen crosslinking. inhibition of LOX and consequent matrix softening lead to TRPV4 activation cascade and increased platelet levels. At the same time, proplatelet formation was reduced on a recombinant enzyme-mediated stiffer collagen. These results suggest a novel mechanism by which MKs, through TRPV4, sense extracellular matrix environmental rigidity and release platelets accordingly.
骨髓中的巨核细胞（MK）浸浴在细胞外基质成分网络中，该网络调节血小板释放进入循环系统。结合生物学和生物工程方法，我们发现，当MK黏附于较软基质时，机械敏感离子通道瞬时受体电位阳离子通道亚家族V成员4（TRPV4）会被激活。这种反应通过引发一系列导致钙内流、β1整合素激活与内化以及Akt磷酸化的事件来促进血小板生成，而在较硬基质上未发现这些反应。赖氨酰氧化酶（LOX）是骨髓基质硬度（胶原蛋白交联）的生理调节因子。抑制LOX并随之使基质软化会导致TRPV4激活级联反应并使血小板水平升高。与此同时, 在重组酶介导的较硬胶原蛋白上，前血小板形成减少。这些结果提示了一种新机制，即巨核细胞通过TRPV4感知细胞外基质环境硬度并相应地释放血小板。
