Mobilization of stem/progenitor cells by sulfated polysaccharides does not require selectin presence

Abstract

Employing carbohydrate ligands, which have been extensively used to block selectin function in vitro and in vivo, we have examined the involvement of such ligands in stem͞progenitor cell mobilization in mice and monkeys. We found that sulfated fucans, branched and linear, are capable of increasing mature white cells in the periphery and mobilizing stem͞progenitor cells of all classes (up to 32-fold) within a few hours posttreatment in a dosedependent manner. To elicit the effect, the presence of sulfate groups was necessary, yet not sufficient, as certain sulfated hexosamines tested (chondroitin sulfates A or B) were ineffective. Significant mobilization of stem͞progenitor cells and leukocytosis was elicited in selectin-deficient mice (L ؊/؊ , PE ؊/؊ , or LPE ؊/؊ ) similar to that of wild-type controls, suggesting that the mode of action of sulfated fucans is not through blockade of known selectins. Other mechanisms have been entertained, in particular, the release of chemokines͞cytokines, including some previously implicated in mobilization. Significant increases were documented in the levels of seven circulating chemokines͞cytokines within a few hours after fucan sulfate treatment and support such a proposition. Additionally, an increase was noted in plasma metalloproteinase (MMP) 9, which might independently contribute to the mobilization process by enzymatically facilitating chemokine͞ cytokine release. Mobilization by sulfated polysaccharides provides a distinct paradigm in the mobilization process and uncovers an additional novel in vivo biological role for sulfated glycans. As similarly sulfated compounds were ineffective in vivo, the data also underscore the fact that polysaccharides with similar structures may elicit diverse in vivo effects.

The integrin αMβ2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization

“…21 While evaluating the role of selectins in the mobilization process, we and others found that fucoidan, a sulfated fucose polymer known to interact with P-and L-selectins and to inhibit leukocyte rolling and inflammatory responses in vivo, [22][23][24] can rapidly mobilize progenitors into the peripheral blood compartment. 25,26 This effect was accentuated in endothelial selectindeficient mice, indicating that the presence of selectins was not required for fucoidan-induced mobilization. Further studies have suggested that fucoidan increased the levels of stromal cell-derived factor (SDF-1 or CXCL12) in the blood, an effect that may contribute to its mobilizing activity.…”

“…Since fucoidan can mobilize progenitors from the BM to the blood compartment in a selectin-independent manner 25,26 and recent experimental evidence has linked mobilization with myeloid cells, 2,5,6,29 we hypothesized that fucoidan might interact with other receptors on the surface of myeloid cells. To investigate this possibility, BMNCs were stained with biotinylated fucoidan (BFuc) and bound fucoidan detected by flow cytometry.…”

Innate immunity as orchestrator of stem cell mobilization

“…28,61 Mobilization could also be achieved by the administration of some types of polysaccharides (for example, zymosan or fucoidans) that in animal models have been demonstrated to efficiently mobilize HSPCs within 1 h after a single injection. 66,67 Elements of innate immunity involved in stem cell mobilization Evidence from our, [41][42][43][44]68 and other laboratories 69,70 indicates that innate immunity orchestrates egress of HSPCs from BM into PB. Innate or natural immunity is inborn and thus naturally present in an organism; it does not require previous sensitization to an antigen.…”

Autonomic regulation of hematopoiesis and cancer

“…Different groups found that the selectin inhibitor fucoidan increased circulating hematopoietic progenitors (HSPCs) independently of selectin function. 6,7 The hypothesis was advanced that sulfated glycans expressed in the BM microenvironment, like sulfatide, might regulate HSC trafficking. Sulfatide, a major component of myelin, is synthetized by the UDPgalactose:ceramide galactosyltransferase (Cgt) enzyme.…”