Granulocyte-Colony-Stimulating Factor Stimulation of Bone Marrow Mesenchymal Stromal Cells Promotes CD34+ Cell Migration Via a Matrix Metalloproteinase-2-Dependent Mechanism

Abstract

Human hematopoietic stem/progenitor cells (HSPCs) can be mobilized into the circulation using granulocytecolony stimulating factor (G-CSF), for graft collection in view of hematopoietic transplantation. This process has been related to bone marrow (BM) release of serine proteases and of the matrix metalloproteinase-9 (MMP-9). Yet, the role of these mediators in HSC egress from their niches remains questionable, because they are produced by nonstromal cells (mainly neutrophils and monocytes/macrophages) that are not a part of the niche. We show here that the G-CSF receptor (G-CSFR) is expressed by human BM mesenchymal stromal/stem cells (MSCs), and that G-CSF prestimulation of MSCs enhances the in vitro trans-stromal migration of CD34 + cells. Zymography analysis indicates that pro-MMP-2 (but not pro-MMP-9) is expressed in MSCs, and that G-CSF treatment increases its expression and induces its activation at the cell membrane. We further demonstrate that G-CSFstimulated migration depends on G-CSFR expression and is mediated by a mechanism that involves MMPs. These results suggest a molecular model whereby G-CSF infusion may drive, by the direct action on MSCs, HSPC egress from BM niches via synthesis and activation of MMPs. In this model, MMP-2 instead of MMP-9 is implicated, which constitutes a major difference with mouse mobilization models.

A Novel Combinatorial Therapy With Pulp Stem Cells and Granulocyte Colony-Stimulating Factor for Total Pulp Regeneration

“…G-CSFR-positive cells represented 59% of the human pulp stem cells (Murakami M, Horibe H, Iohara K et al, manuscript in preparation). Thus, G-CSF, which stimulates migration of bone marrow mesenchymal stem cells, is based on their expression of G-CSFR [5] and may be a potential alternative to SDF-1 for pulp regeneration. Transplantation of stem cells derived from other tissues, bone marrow stromal cells, neuronal stem cells, and amniotic fluid stem cells, with G-CSF into the spinal cord injury results in a better functional and morphological recovery with augmentation of nerve regeneration.…”

Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte‐colony stimulating factor

“…Notably, there were no significant differences in those in vitro effects between bFGF and G‐CSF. Enhanced migration of mesenchymal stem cells (MSCs) mediated by bFGF (Langer et al , ) or G‐CSF (Iohara et al , , ; Yu et al , ; Ponte et al , ; Murakami et al , ) has already been demonstrated separately in distinct cell types. The high stimulatory effect on proliferation and differentiation of MSCs into endothelial cells has been elucidated in bFGF‐supplemented medium (Wu et al , ; Wang et al , ) and in G‐CSF‐supplemented medium.…”

Identification and Characterization of Circulating Variants of CXCL12 from Human Plasma: Effects on Chemotaxis and Mobilization of Hematopoietic Stem and Progenitor Cells

“…However, with the application of G-CSF, the BM progresses to a highly proteolytic microenvironment that is characterized by MMP-2, MMP-9, MMP-14 (MT1-MMP), cathepsin G, neutrophil elastase, and Cterminal processing cathepsin K and carboxypeptidase M [35,39]. In this situation, CXCL12 may be produced as an important proteolytic CXCL12 variant for stem cell mobilization, which has been suggested to switch receptor specificity to CXCR3 [40,41].…”