Caffeic acid phenethyl ester promotes haematopoietic stem/progenitor cell homing and engraftment.
Caffeic acid phenethyl ester promotes haematopoietic stem/progenitor cell homing and engraftment.
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咖啡酸苯乙酯促进造血干/祖细胞归巢和植入
DOI：
10.1186/s13287-017-0708-x
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发表时间：
2017-11-07
影响因子：
7.5
通讯作者：
Pei X
中科院分区：
文献类型：
--
作者：
Chen X;Han Y;Zhang B;Liu Y;Wang S;Liao T;Deng Z;Fan Z;Zhang J;He L;Yue W;Li Y;Pei X
咖啡酸苯乙酯（CAPE）可诱导缺氧诱导因子-1 α（HIF-1α）蛋白的表达。我们确定了CAPE是否具有通过调节骨髓（BM）龛中HIF-1α基因表达来改善造血干/祖细胞（HSPCs）归巢和植入的新功能。对于存活实验，根据指定的时间表，向致死性辐照的C57 BL/6小鼠注射少量BM单核细胞（MNC）和CAPE。使用流式细胞术和集落形成单位（CFU）测定进行归巢效率分析。采用竞争性和非竞争性小鼠移植模型评价腹腔注射CAPE对HSPCs短期和长期植入的影响。为了探讨CAPE促进HSPC归巢的机制，我们在体内阻断HIF-1α活性后，进行了Q-PCR、western blot、免疫组化和CFU测定等实验。CAPE注射显著提高了致死性照射和移植少量BM MNCs后的受体小鼠的存活率。使用HSPC归巢测定，我们发现CAPE显著增加供体HSPC归巢至受体BM。CAPE给药的最佳方案也改善了移植HSPCs的短期和长期植入。CAPE上调HIF-1α、血管内皮生长因子-A（VEGF-A）和基质细胞衍生因子1α（SDF-1α）的表达。HIF-1α抑制剂PX-478阻断了CAPE增强的HSPC归巢，这支持了HIF-1α是CAPE的关键靶点的观点。我们的研究结果表明，CAPE给药促进HSPC归巢和植入，这种作用主要依赖于HIF-1α激活和BM龛中SDF-1α和VEGF-A表达的上调。本文的在线版本（doi：10.1186/s13287-017-0708-x）包含补充材料，可供授权用户使用。
Several studies have suggested that caffeic acid phenethyl ester (CAPE) can induce the expression of hypoxia inducible factor-1α (HIF-1α) protein. We determined whether CAPE has a novel function in improving the homing and engraftment of haematopoietic stem/progenitor cells (HSPCs) by regulating HIF-1α gene expression in the bone marrow (BM) niche. For survival experiments, lethally irradiated C57BL/6 mice were injected with a low number of BM mononuclear cells (MNCs) and CAPE according to the indicated schedule. Homing efficiency analysis was conducted using flow cytometry and colony-forming unit (CFU) assays. The influence of intraperitoneal injection of CAPE on short-term and long-term engraftment of HSPCs was evaluated using competitive and non-competitive mouse transplantation models. To investigate the mechanism by which CAPE enhanced HSPC homing, we performed these experiments including Q-PCR, western blot, immunohistochemistry and CFU assays after in-vivo HIF-1α activity blockade. CAPE injection significantly increased the survival rate of recipient mice after lethal irradiation and transplantation of a low number of BM MNCs. Using HSPC homing assays, we found that CAPE notably increased donor HSPC homing to recipient BM. The subsequent short-term and long-term engraftment of transplanted HSPCs was also improved by the optimal schedule of CAPE administration. Mechanistically, we found that CAPE upregulated the expression of HIF-1α, vascular endothelial growth factor-A (VEGF-A) and stromal cell-derived factor 1α (SDF-1α). The HIF-1α inhibitor PX-478 blocked CAPE-enhanced HSPC homing, which supported the idea that HIF-1α is a key target of CAPE. Our results showed that CAPE administration facilitated HSPC homing and engraftment, and this effect was primarily dependent on HIF-1α activation and upregulation of SDF-1α and VEGF-A expression in the BM niche. The online version of this article (doi:10.1186/s13287-017-0708-x) contains supplementary material, which is available to authorized users.
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