PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells.
PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells.
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DOI：
10.1038/nm.3960
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发表时间：
2015-11
期刊：
影响因子：
82.9
通讯作者：
Lapidot T
中科院分区：
文献类型：
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作者：
Gur-Cohen S;Itkin T;Chakrabarty S;Graf C;Kollet O;Ludin A;Golan K;Kalinkovich A;Ledergor G;Wong E;Niemeyer E;Porat Z;Erez A;Sagi I;Esmon CT;Ruf W;Lapidot T
在骨髓中保留长期再生的造血干细胞（LT-HSC）对于造血和保护免受骨髓毒性损伤是必不可少的。我们报告说，传统上被视为与凝血相关的信号级联反应也控制EPCR+ LT-HSC在骨髓中的保留以及它们通过两种不同的蛋白酶激活受体1（PAR 1）介导的途径招募到血液中。凝血酶-PAR 1信号传导诱导一氧化氮（NO）产生，导致TACE介导的EPCR脱落，增强CXCL 12-CXCR 4诱导的运动性，以及快速干细胞和祖细胞动员。相反，骨髓血管提供富含蛋白C的微环境，其通过限制NO生成、降低Cdc 42活性和增强VLA 4亲和力和粘附来保留EPCR+ LT-HSC。通过活化蛋白C（aPC）-EPCR-PAR 1信号传导抑制NO产生减少祖细胞流出，增加NOlow骨髓EPCR+ LT-HSC保留，并保护小鼠免于化疗诱导的血液学衰竭和死亡。我们的研究揭示了PAR 1和EPCR的新作用，它们控制NO的产生，以平衡具有临床意义的骨髓EPCR+ LT-HSC的维持和募集。
Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance.