A new path to platelet production through matrix sensing.
A new path to platelet production through matrix sensing.
复制标题
通过基质传感进行血小板产生的新路径。
DOI：
10.3324/haematol.2016.161562
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发表时间：
2017-07
期刊：
影响因子：
10.1
通讯作者：
Balduini A
中科院分区：
文献类型：
--
作者：
Abbonante V;Di Buduo CA;Gruppi C;De Maria C;Spedden E;De Acutis A;Staii C;Raspanti M;Vozzi G;Kaplan DL;Moccia F;Ravid K;Balduini A
骨髓（BM）中的巨核细胞（MK）浸入细胞外基质成分网络中，调节血小板释放到循环中。结合生物学和生物工程学的方法，我们发现，激活瞬时受体电位阳离子通道亚家族V成员4（TRPV4），机械敏感的离子通道，诱导MK粘附在较软的基质。这种反应通过触发导致钙内流、β1整联蛋白活化和内化以及Akt磷酸化的级联反应促进血小板生成，这些反应在较硬的基质上未发现。赖氨酰氧化酶（LOX）是通过胶原交联的BM基质硬度的生理调节剂。LOX的体内抑制和随后的基质软化导致TRPV4激活级联反应和血小板水平增加。与此同时，在体外前血小板形成减少重组酶介导的硬胶原蛋白。这些结果提示了MK通过TRPV4感知细胞外基质环境刚性并相应地释放血小板的新机制。
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 via collagen crosslinking. In vivo inhibition of LOX and consequent matrix softening lead to TRPV4 activation cascade and increased platelet levels. At the same time, in vitro 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.
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