Heparan sulfate proteoglycans: A GAGgle of skeletal‐hematopoietic regulators

Abstract

This review summarizes our current understanding of the presence and function of heparan sulfate proteoglycans (HSPGs) in skeletal development and hematopoiesis. Although proteoglycans (PGs) comprise a large and diverse group of cell surface and matrix molecules, we chose to focus on HSPGs owing to their many proposed functions in skeletogenesis and hematopoiesis. Specifically, we discuss how HSPGs play predominant roles in establishing and regulating niches during skeleto-hematopoietic development by participating in distinct developmental processes such as patterning, compartmentalization, growth, differentiation, and maintenance of tissues. Special emphasis is placed on our novel hypothesis that mechanistically links endochondral skeletogenesis to the establishment of the hematopoietic stem cell (HSC) niche in the marrow. HSPGs may contribute to these developmental processes through their unique abilities to establish and mediate morphogen, growth factor, and cytokine gradients; facilitate signaling; provide structural stability to tissues; and act as molecular filters and barriers. Developmental TRIBUTE TO DR. ELIZABETH D. HAYDr. Elizabeth Dexter Hay, "Betty" to her friends, would often introduce her seminars on extracellular matrix (ECM) and epithelial-mesenchymal cell transformations by showing pictures of her cats asleep intertwined with a blanket. She would use this analogy to highlight the intimate association that exists between a cell and its ECM during development. She was a pioneer who brought forth the notion that the ECM is not just a static "stuffing between cells," but has interactive and instructive roles in development.Betty's contribution to the ECM field began with her seminal discoveries in the emerging field of electron microscopy. She worked with Keith Porter, George Palade, Don Fawcett, Susumo Ito, Jean-Paul Revel, and others to unravel the intricate microanatomy of the cell and its ECM. Once, when working with Jean-Paul Revel to extend autoradiography to the ultrastructural level, Betty noticed that tritiated proline was incorporated into collagen in the ECM outside of the cartilage cells. Betty went on to demonstrate that epithelial cells, as well as other non-fibroblastic cells, do secrete collagen. Moreover, in her descriptions of the development and structure of the various matrices, Betty brought forth the hypothesis that the ECM interacts with cells, and that through these interactions, the cells are instructed to modify their behavior. This notion was showcased in the "Epithelial-Mesenchymal Transformation Model" she proposed to describe the dramatic morphological transformations of epithelial cells suspended in collagen gels.Among her numerous scientific accomplishments, Betty can be considered a founder of the field of cell biology. Moreover, through her personal attributes and interactions with col- leagues and her protegees, Betty has set the standard for many a scientist. This review is a tribute to Betty, a friend, colleague, and mentor, and highlights our developing premi...

Enhanced Osteogenesis in Cocultures with Human Mesenchymal Stem Cells and Endothelial Cells on Polymeric Microfiber Scaffolds

“…GAGs have a variety of biological functions necessary for osteogenesis and cell-to-cell communications. 41 One possible reason for increased GAG production observed in cocultures in the present study could be residual heparin sulfate, which is a component of vascular basal media commonly used for HUVEC cultivation and the media used for HUVEC culture in the present study. However, no GAGs were detected in HUVEC monoculture (Fig.…”

The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment

“…65,66 Continuous remodeling of trabecular bone by osteoclasts liberates cytokines that are immobilized by proteoglycans and support HSC maintenance. 67 This scenario is supported by studies, showing that HSCs express a calcium-sensing receptor (CaR) and preferentially home to and are retained at calcium-enriched regions where trabecular bone is being remodeled. 68 Osteoblasts can expand long-term cultureinitiating cells in vitro, and are shown to regulate the number of HSCs in vivo.…”

“…Mutations in perlecan or collagen-X indirectly attenuate hematopoiesis via disruption of the endochondral ossification processes, resulting in marrow aplasia and lymphopenia. 67,138 In addition, loss of function mutations in the proteoglycan glypican-3 perturbed hematopoiesis. 139 Heparan sulfate modification of proteoglycans is also an essential element in the BM, critical for the establishment of the HSPC niche.…”

“…139 Heparan sulfate modification of proteoglycans is also an essential element in the BM, critical for the establishment of the HSPC niche. 67,140,141 In addition, hyaluronic acid, the non-sulfated proteoglycan, is required for in vitro hematopoiesis and enhances hematopoiesis in the bone marrow after 5-fluorouracil (5-FU) treatment. 142 Together, this illustrates that proteoglycans and collagens are essential for HSPC maintenance.…”

“…[115][116][117][118][119] Important for ECM integrity are also the proteoglycans with their large glycosaminoglycan (GAG) sidechains, including hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate and heparin. 120 Other ECM (associated) molecules are the soluble or membrane bound glycoproteins of the sialomucin family, including CD34, glycosylation dependent cell adhesion molecule1 (GlyCAM1), mucosal vascular addressin CAM1 (Mad-CAM1), platelet-selectin glycoprotein ligand (PSGL1/CD162), sialophorin (SPN/CD43), CD45RA and CD164. Essential mediators of the cell-cell and cell-matrix interactions in the BM are integrins and selectins, [121][122][123] whereas membrane bound receptors of the immunoglobin superfamily, including intercellular adhesion molecule-1 (ICAM1; CD54), vascular cell adhesion molecule-1 (VCAM1; CD105) and CD166, also shape the bone marrow niche.…”