Novel evidence that crosstalk between the complement, coagulation and fibrinolysis proteolytic cascades is involved in mobilization of hematopoietic stem/progenitor cells (HSPCs)
Novel evidence that crosstalk between the complement, coagulation and fibrinolysis proteolytic cascades is involved in mobilization of hematopoietic stem/progenitor cells (HSPCs)
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DOI：
10.1038/leu.2014.115
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发表时间：
2014-11-01
期刊：
影响因子：
11.4
通讯作者：
Ratajczak, M. Z.
中科院分区：
文献类型：
--
作者：
Borkowska, S.;Suszynska, M.;Ratajczak, M. Z.
血液蛋白水解酶在造血干/祖细胞(HSPC)动员中的作用尚不清楚。正如先前报道的那样，补体级联(Comc)的激活和C5被C5转换酶裂解是C5a释放的启动事件，C5a在HSPC从骨髓(BM)进入外周血(PB)的过程中起着至关重要的作用，这也解释了为什么C5缺陷小鼠动员能力较差。在这里，我们提供了证据，在粒细胞集落刺激因子和AMD3100诱导的动员过程中，不仅COMC而且还有另外两个进化上古老的蛋白水解酶级联，即凝血级联(COAC)和纤溶级联(FIBC)，被激活。通过C5a的产生、凝血酶原时间和活化部分凝血活酶时间的减少以及纤溶酶/抗纤溶酶和凝血酶/抗凝血酶浓度的升高来衡量这三个级联反应的激活程度。更重要的是，COAC和FIBC分别通过产生凝血酶和纤溶酶来提供C5转换酶活性，这解释了为什么C3缺陷小鼠的HSPC动员没有受到损害，因为C3缺陷小鼠不会产生Comc生成的C5a转换酶。我们的观察揭示了COAC和FIBC如何调节干细胞动员，并可能导致在动员不良的人中开发更有效的动员策略。此外，众所周知，所有这些级联反应在HSPC从骨髓动员到PB的所有情况下(例如感染、组织/器官损伤或剧烈运动)都被激活，并表现出昼夜节律，因此它们肯定参与了应激诱导的和PB中HSPC运输的昼夜变化。
The role of blood proteinases in the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not well understood. As previously reported, activation of the complement cascade (ComC) and cleavage of C5 by C5 convertase are enabling events in the release of C5a that plays a crucial role in the egress of HSPCs from bone marrow (BM) into peripheral blood (PB) and explains why C5-deficient mice are poor mobilizers. Here we provide evidence that during granulocyte colony-stimulating factor-and AMD3100-induced mobilization, not only the ComC but also two other evolutionarily ancient proteolytic enzyme cascades, the coagulation cascade (CoaC) and the fibrynolytic cascade (FibC), become activated. Activation of all three cascades was measured by generation of C5a, decrease in prothrombin time and activated partial thromboplastin time as well as an increase in the concentrations of plasmin/antiplasmin and thrombin/antithrombin. More importantly, the CoaC and FibC, by generating thrombin and plasmin, respectively, provide C5 convertase activity, explaining why mobilization of HSPCs in C3-deficient mice, which do not generate ComC-generated C5a convertase, is not impaired. Our observations shed more light on how the CoaC and FibC modulate stem cell mobilization and may lead to the development of more efficient mobilization strategies in poor mobilizers. Furthermore, as it is known that all these cascades are activated in all the situations in which HSPCs are mobilized from BM into PB (for example, infections, tissue/organ damage or strenuous exercise) and show a circadian rhythm of activation, they must be involved in both stress-induced and circadian changes in HSPC trafficking in PB.