MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

Abstract

The online version of this article has a Supplementary Appendix. BackgroundMobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. Design and MethodsWe analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. ResultsWe show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. ConclusionsOur results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

“…[29][30][31] In addition, miR-126 was shown to coregulate the expansion and mobilization of hematopoietic stem cells and progenitor cells. 32,33 We hypothesized that miR-126 overexpression in the hematopoietic compartment of mice can enhance the vasoprotective potential of these progenitors and that this will translate to decreased renal injury.…”

MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium

“…6C). Although VCAM1 and CCL2 have been previosly shown to be miR-126 gene targets in different endothelial and non-endothelial cell types182138394041424344, it has not been reported in human brain endothelium. We tested the effects of miR-126 and miR-126*, using gain-and loss-of-function approach, on their mRNA expressed in hCMEC/D3 cells respective targets at the protein level following the experimental design depicted in Fig.…”

Circulating microRNAs in hematological diseases: principles, challenges, and perspectives

“…Zernecke et al 79 were the first to show that miR-126-enriched apoptotic bodies shed by endothelial cells are taken up by neighboring vascular cells, where they promote proliferation as well as production of CXCL12, a chemokine known to counteract apoptosis. Similarly, the relevance of miRNA trafficking in the bone marrow compartment was highlighted by Salvucci et al, 80 who demonstrated that granulocyte colony-stimulating factor promotes the accumulation of miR-126-containing microvesicles in the bone marrow and thereby targets the expression of surface vascular cell adhesion molecule-1 on early hematopoietic cells. 80 This novel regulatory layer underlines the growing impact of circulating miRNAs on stem cell physiology.…”

“…Similarly, the relevance of miRNA trafficking in the bone marrow compartment was highlighted by Salvucci et al, 80 who demonstrated that granulocyte colony-stimulating factor promotes the accumulation of miR-126-containing microvesicles in the bone marrow and thereby targets the expression of surface vascular cell adhesion molecule-1 on early hematopoietic cells. 80 This novel regulatory layer underlines the growing impact of circulating miRNAs on stem cell physiology.…”