Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling.
Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling.
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DOI：
10.1111/nyas.13013
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发表时间：
2016-04
影响因子：
5.2
通讯作者：
Lapidot T
中科院分区：
文献类型：
--
作者：
Gur-Cohen S;Kollet O;Graf C;Esmon CT;Ruf W;Lapidot T
内皮细胞和造血细胞的共同发育起源通过几种细胞表面受体的共表达来体现。成年小鼠骨髓 (BM) 长期再生造血干细胞 (LT-HSC) 具有最高的再生和自我更新潜力，表达内皮蛋白 C 受体 (EPCR)，可用作分离它们的标记。内皮细胞中的EPCR/PAR1信号传导具有抗凝和抗炎作用，而凝血酶/PAR1信号传导则诱导凝血和炎症。最近的研究定义了两个新的 PAR1 介导的信号级联，可调节 EPCR+ LT-HSC BM 保留和流出。 EPCR/PAR1 信号传导通过限制一氧化氮 (NO) 产生、维持 NO 低 LT-HSC BM 保留以及增加 VLA4 表达、亲和力和粘附力，促进 LT-HSC BM 重新增殖、保留、存活和化疗耐药性。相反，急性应激和临床动员会上调凝血酶的生成并激活不同的 PAR1 信号传导，从而克服 BM EPCR+ LT-HSC 滞留，诱导其招募到血流中。凝血酶/PAR1 信号传导诱导 NO 生成、TACE 介导的 EPCR 脱落以及 CXCR4 和 PAR1 的上调，从而导致 CXCL12 介导的干细胞和祖细胞动员。这篇综述讨论了传统上被认为与凝血相关的因子的新作用，这些因子在 BM 中独立作用，调节骨和造血祖细胞中的 PAR1 信号传导，通过控制 NO 的产生来控制它们的命运。
The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/PAR1 signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation. Recent studies define two new PAR1-mediated signaling cascades that regulate EPCR+ LT-HSC BM retention and egress. EPCR/PAR1 signaling facilitates LT-HSC BM repopulation, retention, survival, and chemotherapy resistance by restricting nitric oxide (NO) production, maintaining NOlow LT-HSC BM retention with increased VLA4 expression, affinity, and adhesion. Conversely, acute stress and clinical mobilization upregulate thrombin generation and activate different PAR1 signaling which overcomes BM EPCR+ LT-HSC retention, inducing their recruitment to the bloodstream. Thrombin/PAR1 signaling induces NO generation, TACE-mediated EPCR shedding, and upregulation of CXCR4 and PAR1, leading to CXCL12-mediated stem and progenitor cell mobilization. This review discusses new roles for factors traditionally viewed as coagulation related, which independently act in the BM to regulate PAR1 signaling in bone- and blood-forming progenitor cells, navigating their fate by controlling NO production.
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影响因子：
23.9
作者：
Butler JM;Nolan DJ;Vertes EL;Varnum-Finney B;Kobayashi H;Hooper AT;Seandel M;Shido K;White IA;Kobayashi M;Witte L;May C;Shawber C;Kimura Y;Kitajewski J;Rosenwaks Z;Bernstein ID;Rafii S
通讯作者：
Rafii S
影响因子：
11.4
作者：
Dar, A.;Schajnovitz, A.;Lapid, K.;Kalinkovich, A.;Itkin, T.;Ludin, A.;Kao, W-M;Battista, M.;Tesio, M.;Kollet, O.;Cohen, N. N.;Margalit, R.;Buss, E. C.;Baleux, F.;Oishi, S.;Fujii, N.;Larochelle, A.;Dunbar, C. E.;Broxmeyer, H. E.;Frenette, P. S.;Lapidot, T.
通讯作者：
Lapidot, T.
影响因子：
20.3
作者：
Colognato, R;Slupsky, JR;Simmet, T
通讯作者：
Simmet, T
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.4
作者：
Borkowska, S.;Suszynska, M.;Ratajczak, M. Z.
通讯作者：
Ratajczak, M. Z.