Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells

Abstract

It was previously reported that treatment with the sulfated polysaccharide fucoidan or the structurally similar dextran sulfate increased circulating mature white blood cells and hematopoietic progenitor/stem cells (HPCs) in mice and nonhuman primates; however, the mechanism mediating these effects was unclear. It is reported here that plasma concentrations of the highly potent chemoattractant stromal-derived factor 1 (SDF-1) increase rapidly and dramatically after treatment with fucoidan in monkeys and in mice, coinciding with decreased levels in bone marrow. In vitro and in vivo data suggest that the SDF-1 increase is due to its competitive displacement from heparan sulfate proteoglycans that sequester the chemokine on endothelial cell surfaces or extracellular matrix in bone marrow and other tissues. Although moderately increased levels of interleukin-8, MCP1, or MMP9 were also present after fucoidan treatment, studies in gene-ablated mice (GCSFR ؊/؊ , MCP1 ؊/؊ , or MMP9 ؊/؊ ) and the use of metalloprotease inhibitors do not support their involvement in the concurrent mobilization. Instead, SDF-1 increases, uniquely associated with sulfated glycan-mobilizing treatments and not with several other mobilizing agents tested, are likely responsible. To the authors' knowledge, this is the first published report of disrupting the SDF-1 gradient between bone marrow and peripheral blood through a physiologically relevant mechanism, resulting in mobilization with kinetics similar to other mobilizing CXC chemokines. The study further underscores the importance of the biological roles of carbohydrates. IntroductionStromal-derived factor 1 (SDF-1) is a highly potent chemoattractant both in vitro and in vivo for mature leukocytes and hematopoietic progenitor/stem cells (HPCs), which carry its receptor CXCR4. [1][2][3][4][5][6][7] This highly conserved chemokine is constitutively expressed by virtually all tissues, 8 including bone marrow (BM). 3 It is expressed as 2 alternatively spliced isoforms, the predominant ␣ form and the ␤ form containing 4 additional amino acids at the C terminus, each possessing a heparin-binding domain. 9,10 The SDF-1-CXCR4 interaction plays a dominant role in hematopoiesis, and mice deficient in either gene die in utero exhibiting defects in B-cell lymphopoiesis and BM myelopoiesis. 4,5 Additionally, a critical role for CXCR4 on human cells in engraftment to the BM of nonobese diabetic/severe combined immunodeficiency mice 6,7 has been shown. Although involvement of SDF-1 in mobilization-the egress of HPCs from the BM to the peripheral blood (PB)-has also been speculated, direct evidence has only recently been obtained in mice using a synthetic SDF-1 analog 11 or following injection with an adenovirus expressing human SDF-1. 12 Previously, we reported that the sulfated polysaccharide fucoidan (FucS) and the structurally similar dextran sulfate (DexS) can elevate circulating white blood cells (WBCs) and mobilize HPCs within hours in a selectin-independent manner in mice and nonhuman primates. 13...

Endothelial progenitor cells in pterygium pathogenesis

“…30,31 SDF-1 is known to mediate the mobilization and migration of bone marrow-derived progenitor cells in vivo. 32 SP has also been shown to have a stimulatory effect on human bone marrow stem cells in vitro by interacting with bone marrow supporting stromal cells. 33 Therefore, it is possible to speculate that an increase in VEGF and SP levels may stimulate bone marrow, and enhance progenitor cell mobilization.…”

Expression of Stromal Cell-Derived Factor-1 and of Its Receptor CXCR4 in Liver Regeneration from Oval Cells in Rat

“…37 To establish a role of SDF-1 in hepatic regeneration from oval cells, rats were injected with fucoidan. This sulfated polysaccharide binds to SDF-1, releases the chemokine from cell membrane-associated heparan sulfate proteoglycans, 27 and could therefore inhibit its biological activity. Indeed, in our AAF/PH model, fucoidan markedly decreased oval cell accumulation in a majority of treated rats, suggesting that SDF-1 promotes the activation of Hering duct-located quiescent stem cells into oval cells and/or stimulates oval cell growth.…”

“…27 These experiments were performed in Wistar rats because preliminary trials showed that this strain tolerated this compound better than Fischer rats. Livers were examined after 4 days of a treatment which was well tolerated, as judged by the absence of difference in the weight of treated and control animals at the end of the experiment.…”

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

“…Both sustained elevations of SDF-1 in NOD/SCID mice delivered by an adenoviral vector delivery system [34][35][36] , and chronic administration to the animals of SDF-1 peptide analogs 37,38 , result in mobilization of stem/ progenitor cells. In addition, increased plasma SDF-1 levels are also observed during mobilization induced by sulfated glycans 39 . Although G-CSF-induced stem/progenitor cell mobilization is not associated with increased levels of SDF-1 in the blood, this treatment reduces the levels of SDF-1 in the marrow and alters CXCR4 expression by stem/progenitor cells 40,41 by inducing a proteolytic environment 42 .…”