Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

Greenbaum, Adam; Link, Daniel C.

doi:10.1038/leu.2010.248

Cited by 202 publications

(173 citation statements)

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“…Several studies have documented that CXCR4 antagonists promote HSPC mobilization. 2,18,46 Based on the observation that G-CSF was ineffective at enhancing HSPC mobilization to blood and spleen of mice with CXCR4 -/-bone marrows, but that an antagonist of VLA4/VCAM1 induced a 2-fold increase in HSPC mobilization, 17 it was suggested that G-CSF is ineffective at mobilizing CXCR4-null HSPC. An alternative explanation, supported by the current results, is that the absence of CXCR4 on myeloid lineage cells prevents G-CSF-induced neutrophil/monocyte mobilization, which is indirectly required for HSPC mobilization by G-CSF as these cells are a source of miR-containing microvescicles.…”

Section: Discussionmentioning

confidence: 99%

“…In the clinical setting, granulocyte colony-stimulating factor (G-CSF) is the most commonly used inducer of HSPC mobilization, which has become the preferred source of HSPC for autologous and allogeneic hematopoietic reconstitution. 2,3 Although it is effective and safe, G-CSF mobilizes committed myeloid cells in vast excess of HSPC, and these cells are mobilized only after 5 to 7 days of treatment. 4 Thus, a better understanding of the mechanisms of action of G-CSF could provide a means to pursue a more selective and rapid mobilization of HSPC.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies suggested that CXCR4 is critical to mobilization of hematopoietic progenitors by G-CSF, 17 but other mechanisms have also been proposed and conclusive evidence is lacking. 2,7,20 Based on the observation that neutrophils and monocytes are critical to HSPC mobilization by G-CSF, we hypothesized that at least some of the changes induced by G-CSF on these cells may serve to promote the accompanying HSPC mobilization. We further considered the possibility that agents which more selectively promote the mobilization of HSPC in preference to neutrophils, such as BIO5192 a small molecule inhibitor of very latent antigen 4 (VLA4; also known as α4b1 integrin) binding to vascular cell adhesion molecule 1 (VCAM1) 21 and antibodies to VLA4 or VCAM1, [22][23][24][25][26] may provide valuable mechanistic insights into G-CSF-induced HSPC mobilization.…”

Section: Introductionmentioning

confidence: 99%

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

Salvucci

Jiang²,

Gasperini³

et al. 2012

Haematologica

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Salvucci

Jiang²,

Gasperini³

et al. 2012

Haematologica

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“…In HSPC mobilization, cytokine administration promotes the egress of stem and progenitor cells into the peripheral circulation (1). In HSPC transplantation, cells are transfused into the venous circulation of the recipient and home to the marrow for engraftment (2).…”

mentioning

confidence: 99%

Implantable microenvironments to attract hematopoietic stem/cancer cells

Lee

Milwid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

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The environments that harbor hematopoietic stem and progenitor cells are critical to explore for a better understanding of hematopoiesis during health and disease. These compartments often are inaccessible for controlled and rapid experimentation, thus limiting studies to the evaluation of conventional cell culture and transgenic animal models. Here we describe the manufacture and image-guided monitoring of an engineered microenvironment with user-defined properties that recruits hematopoietic progenitors into the implant. Using intravital imaging and fluorescence molecular tomography, we show in real time that the cell homing and retention process is efficient and durable for short-and longterm engraftment studies. Our results indicate that bone marrow stromal cells, precoated on the implant, accelerate the formation of new sinusoidal blood vessels with vascular integrity at the microcapillary level that enhances the recruitment hematopoietic progenitor cells to the site. This implantable construct can serve as a tool enabling the study of hematopoiesis.

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“…Granulocyte colony-stimulating factor (G-CSF) suppresses osteoblast lineage cells in the endosteal BM niches, leading to reduced levels of signaling molecules such as CXCL12, VLA-4, and c-Kit, which are essential for HSC retention (Winkler and Levesque, 2006;Winkler et al, 2010;Greenbaum and Link, 2011), resulting in the release of immature HSCs into circulation (Aiuti et al, 1997;Whetton and Graham, 1999). Repeated treatment results in the release of a considerable number of CD34 + cells into the peripheral blood, which can be harvested and subsequently used for patients requiring stem cell transplants (Bensinger et al, 1996;Elfenbein and Sackstein, 2004).…”

mentioning

confidence: 99%

Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

Huston

Riegman²,

Yadak³

et al. 2014

Human Gene Therapy

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Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg-/ -mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin -) cells or Il2rg -/ -Lin -cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.

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Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

Cited by 202 publications

References 100 publications

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

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

Implantable microenvironments to attract hematopoietic stem/cancer cells

Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

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