Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver
Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver
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DOI：
10.1182/blood-2009-08-240903
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发表时间：
2010-07-29
期刊：
影响因子：
20.3
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Iwasaki, Hiroko;Arai, Fumio;Suda, Toshio
造血干细胞 (HSC) 维持在成人骨髓中的特殊位置。然而，胎儿肝脏（FL）中的生态位和HSC维持机制仍不清楚。在这里，我们使用表达内皮蛋白 C 受体 (EPCR) 的 HSC 来研究小鼠 FL 中 HSC 维持的生态位和分子机制。活化蛋白 C (APC) 对 EPCR(+) HSC 的抗凋亡作用以及这些细胞中蛋白酶激活受体 1 (Par-1) mRNA 的表达表明细胞保护性 APC/EPCR/Par-1 通路参与了 HSC 的维持。免疫组织化学显示，EPCR(+) 细胞定位于 Lyve-1(+) 正弦网络附近或整合于其中，其中 APC 和细胞外基质 (ECM) 丰富，表明 FL 中的 HSC 维持在富含 APC 和 ECM 的窦周微环境中。 EPCR(+) HSCs处于相对缓慢的循环状态，与其p57和p18的高表达水平一致。此外，EPCR(+) HSCs 的长期重建活性在短期培养后显着降低，但与 FL 来源的 Lyve-1(+) 细胞的饲养层共培养时则没有显着降低，这表明 FL HSCs 自我更新活性的维持很大程度上取决于与窦周生态位的相互作用。总之，EPCR(+) HSC 位于小鼠 FL 的窦周微环境中。 （血。2010；116(4)：544-533）
Hematopoietic stem cells (HSCs) are maintained in specialized niches in adult bone marrow. However, niche and HSC maintenance mechanism in fetal liver (FL) still remains unclear. Here, we investigated the niche and the molecular mechanism of HSC maintenance in mouse FL using HSCs expressing endothelial protein C receptor (EPCR). The antiapoptotic effect of activated protein C (APC) on EPCR(+) HSCs and the expression of protease-activated receptor 1 (Par-1) mRNA in these cells suggested the involvement of the cytoprotective APC/EPCR/Par-1 pathway in HSC maintenance. Immunohistochemistry revealed that EPCR(+) cells were localized adjacent to, or integrated in, the Lyve-1(+) sinusoidal network, where APC and extracellular matrix (ECM) are abundant, suggesting that HSCs in FL were maintained in the APC- and ECM-rich perisinusoidal niche. EPCR(+) HSCs were in a relatively slow cycling state, consistent with their high expression levels of p57 and p18. Furthermore, the long-term reconstitution activity of EPCR(+) HSCs decreased significantly after short culture but not when cocultured with feeder layer of FL-derived Lyve-1(+) cells, which suggests that the maintenance of the self-renewal activity of FL HSCs largely depended on the interaction with the perisinusoidal niche. In conclusion, EPCR(+) HSCs resided in the perisinusoidal niche in mouse FL. (Blood. 2010; 116(4): 544-533)