Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

Abstract

Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.

Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives

“…Current efforts toward increasing the yield of transduced cells comprise more effective mobilization and collection regimes, using antagonists of the CXCL12/CXCR4 axis, such as Plerixafor (Broxmeyer et al, 2005), and of the VLA-4/VCAM-1 axis (Ghobadi et al, 2018), which mediate HSPC homing and retention in the marrow niche, and/or granulocyte colony-stimulating factor (G-CSF) and CXCR2 agonists, such as GROb, acting on neutrophils and resulting in MMP-9 secretion, matrix digestion and HSPC release (Hoggatt et al, 2018), and ex vivo expansion of the collected HSPC (see below). The HSPC source, with mobilized peripheral blood now preferred over bone marrow, and the mobilization protocol affect the total amount and proportion of long-term repopulating versus committed progenitor cells in the harvest.…”

Peripheral Blood Stem Cell Mobilization: a Look Ahead

“…With the goal of developing a safe, rapid single day mobilization regimen, combination mobilization with the CXCR4 antagonist AMD3100/plerixafor and the CXCR2 ligand GROβ, previously shown to mobilize HSPC in mice and rhesus monkeys [18;69;70] and recently also in man [70] was explored. While the CXCR4 signaling axis has been a focus of mechanism of HSPC mobilization, particularly associated with the action of G-CSF the chemokine ligands of the CXCR2 receptor, notably GROβ and IL8, induce rapid HSPC mobilization.…”

“…Single combined injection of GROβ plus AMD3100 mobilized more HSPC in 15 minutes than the number of HSPC mobilized by G-CSF in a 4 day regimen in mice [70]. Extensive biochemical, molecular and genetic evidence all confirmed crosstalk between these neutrophil receptors.…”

“…However, in studies comparing HSC number in the GROβ plus AMD3100 versus G-CSF mobilized grants, the GROβ plus AMD3100 graft actually contained fewer phenotypically define HSC. Competitive transplants using highly purified HSC from mice mobilized with GROβ plus AMD3100 or G-CSF and transplanted with the exact same number of HSC showed the HSC from GROβ plus AMD3100 mobilized mice to be twice as competitive as those from mice mobilized with G-CSF, and indicate that GROβ plus AMD3100 mobilizes a distinct highly engraftable HSC population (heHSC) with superior competitiveness [70]. RNA sequencing of these heHSC indicated that they had a distinct transcriptome compared to HSC mobilized by G-CSF.…”

Cobalt protoporphyrin IX increases endogenous G‐ CSF and mobilizes HSC and granulocytes to the blood

“…Apart from G-CSF, many other agents, such as stromal cell-derived factor 1a (Hattori et al, 2001;Devine et al, 2008), stem cell factor (Andrews et al, 1992), interleukin 6 (IL-6) (Pojda & Tsuboi, 1990), IL-8 (Laterveer et al, 1995), Grob (Pelus & Fukuda, 2006;Fukuda et al, 2007), or granulocyte-macrophage colony-stimulating factor (GM-CSF) (Gianni et al, 1989) can act as mobilizing factors (reviewed in (Lapid et al, 2008)). Recently, Hoggatt et al (2018) reported rapid mobilization of highly engrafting stem cells with a single injection of Grob and AMD3100 combination.…”