Heparan sulfate proteoglycans as key regulators of the mesenchymal niche of hematopoietic stem cells

Abstract

The complex microenvironment that surrounds hematopoietic stem cells (HSCs) in the bone marrow niche involves different coordinated signaling pathways. The stem cells establish permanent interactions with distinct cell types such as mesenchymal stromal cells, osteoblasts, osteoclasts or endothelial cells and with secreted regulators such as growth factors, cytokines, chemokines and their receptors. These interactions are mediated through adhesion to extracellular matrix compounds also. All these signaling pathways are important for stem cell fates such as self-renewal, proliferation or differentiation, homing and mobilization, as well as for remodeling of the niche. Among these complex molecular cues, this review focuses on heparan sulfate (HS) structures and functions and on the role of enzymes involved in their biosynthesis and turnover. HS associated to core protein, constitute the superfamily of heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix of all tissues. The key regulatory effects of major medullar HSPGs are described, focusing on their roles in the interactions between hematopoietic stem cells and their endosteal niche, and on their ability to interact with Heparin Binding Proteins (HBPs). Finally, according to the relevance of HS moieties effects on this complex medullar niche, we describe recent data that identify HS mimetics or sulfated HS signatures as new glycanic tools and targets, respectively, for hematopoietic and mesenchymal stem cell based therapeutic applications.

Compositional and structural analysis of glycosaminoglycans in cell-derived extracellular matrices

“…Based on the structure and sulfation level of the repeating disaccharide, GAGs can be generally classified into four families that include heparan sulfate (HS), chondroitin sulfate (CS), keratan sulfate (KS) and hyaluronic acid (HA) [18,19], Proteoglycans and respective GAGs localize mainly in cell membranes and reside within the ECM, acting as molecular co-receptors in cell signaling for cell-cell and cell-ECM interactions important for cell survival and differentiation [18], The negatively charged GAGs are also associated with the maintenance of the biomechanical properties of tissues through controlling of hydration and swelling pressure, allowing tissues to absorb compressional forces. Additionally, the sulfation patterns in the GAG chains play crucial roles by allowing interactions, mainly of an ionic nature, with growth factors, cell surface receptors, enzymes, cytokines, chemokines and proteins that are associated with several biological processes, such as development, disease, cell growth and differentiation and microbial pathogenesis [20][21][22][23]. In fact, GAGs role in controlling stem cell fate through modulation of important signaling pathways such as FGF signaling was previously suggested [18,21,24], Additionally, the effects of different GAGs in MSC proliferation and differentiation through mediation of growth factor activity have also been reported in the literature [25][26][27][28], Therefore, the structural and growth factor sequestering/activation properties of GAGs make these biomolecules promising materials for a broad range of tissue engineering applications [19,20,29], As major components of cartilage, GAGs, mainly CS and HA, have been incorporated in tissue engineering scaffolds to more effectively mimic the natural ECM and improve the quality of the generated tissue [30][31][32].…”

Role of nanoparticle size and sialic acids in the distinct time-evolution profiles of nanoparticle uptake in hematopoietic progenitor cells and monocytes

“…cell surface proteoglycans [15], and on the physicochemical properties of NPs, such as size [16, 17]. Alike all vertebrate’s cells, HPCs express glycan molecules at their outer membrane [18, 19]. These are negatively charged surface molecules and constitute a group of transmembrane glycoproteins that can have major influences in the interaction with extracellular structures and molecules [20].…”

Heparanase Facilitates PMA-Induced Megakaryocytic Differentiation in K562 Cells via Interleukin 6/STAT3 Pathway

“…In this microenvironment, HSPGs are believed not to be simply passive structural components of ECM and cells rather they are multifunctional molecules regulating cell behaviors by fine tuning the functions of many cytokines. As the only known endo-β-D-glucuronidase that cleaves HS, the major function of HPSE is through modulation of HS molecular structure, leading to release or activation of a wide range of HBPs, 33 including the cytokines involved in megakaryopoiesis. Our previous studies revealed that overexpression of HPSE in mice led to a substantial increase in the number and activity of platelets, which is at least partially, contributed by upregulating TPO expression in the liver.…”