Caffeic acid phenethyl ester promotes haematopoietic stem/progenitor cell homing and engraftment

Abstract

BackgroundSeveral 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.MethodsFor 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.ResultsCAPE 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0708-x) contains supplementary material, which is available to authorized users.

Past, present, and future efforts to enhance the efficacy of cord blood hematopoietic cell transplantation

“…HIF-1α is stabilized in HSCs and regulates HSC activity/quiescence 131, 132 . Pharmacological increases in HIF-1α promote HSC homing and engraftment also by upregulating surface CXCR4 expression 133 . CXCR4 expression upregulation results from HIF-1α binding with hypoxia response elements, located at –1.3 kb from the transcription start site of the CXCR4 promoter region.…”

Progress towards improving homing and engraftment of hematopoietic stem cells for clinical transplantation

“…Furthermore, it was demonstrated that HIF-1α is required for dmPGE2 mediated CXCR4 upregulation, enhanced HSC migration and homing. Recent work from another group reported that caffeic acid phenethyl ester (CAPE) administration promotes HSC homing and engraftment by inducing expression of HIF-1α [45]. CAPE treatment upregulated protein levels of HIF-1α and CXCL12 in BM endothelial cells.…”

Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell

“… Target/signaling Expansion effect Ref. Rapamycin mTOR ‒ 112 Garcinol/isogarcinol HATs 4.5-/7.4-fold HSCs 2.5-fold SRCs (garcinol) 118 TSA HDAC 2.5-fold CD34 + 40-fold CD34 + CD90 + 132 EchA ROS inhibition PI3K/AKT activation 1.33-fold CD34 + 1.7-fold CFUs 137 ASPP049 Hippo signaling ∼1.5-fold CD34 + CD38 − ∼2-fold hCD45 + 143 Chrysin p19, p57, MNDA, NR4A2, HOXB4 ∼1.5-fold HSCs 2.7-fold SRCs 145 Resveratol ‒ 1.84-fold CD34 + /CD133 + 138 , 139 , 140 CAPE HIF-1 α , SDF-1 α and VEGF-A 1.47-fold CFUs 1.77-fold SRCs 141 , 142 5-HT Apoptosis inhibition 1.73-fold CFU-F 12.2-fold CD34 + 146 α -Tocopherol ERK1/2 2-fold LSKs 147 ATRA RA receptor 4-fold CFUs 148 , 149 …”

“…18 ) also acts as an antioxidant, derived from propolis. 60 promoted ex vivo CB-HSCs expansion, homing and engraftment in vivo , mediated by up-regulation of HIF-1 α and vascular endothelial growth factor-A (VEGF-A) 141 , 142 .…”