Hyaluronan – A Functional and Structural Sweet Spot in the Tissue Microenvironment

Abstract

Transition from homeostatic to reactive matrix remodeling is a fundamental adaptive tissue response to injury, inflammatory disease, fibrosis, and cancer. Alterations in architecture, physical properties, and matrix composition result in changes in biomechanical and biochemical cellular signaling. The dynamics of pericellular and extracellular matrices, including matrix protein, proteoglycan, and glycosaminoglycan modification are continually emerging as essential regulatory mechanisms underlying cellular and tissue function. Nevertheless, the impact of matrix organization on inflammation and immunity in particular and the consequent effects on tissue healing and disease outcome are arguably under-studied aspects of adaptive stress responses. Herein, we review how the predominant glycosaminoglycan hyaluronan (HA) contributes to the structure and function of the tissue microenvironment. Specifically, we examine the evidence of HA degradation and the generation of biologically active smaller HA fragments in pathological settings in vivo. We discuss how HA fragments versus nascent HA via alternate receptor-mediated signaling influence inflammatory cell recruitment and differentiation, resident cell activation, as well as tumor growth, survival, and metastasis. Finally, we discuss how HA fragmentation impacts restoration of normal tissue function and pathological outcomes in disease.

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

“…HA is retained as a pericellular coat after its synthesis, anchored to the cell surface via the synthase enzyme or through binding to a surface receptor, and certain amount cleaved by hyaluronidase is released from the pericellular matrix and incorporated as an integral component of the ECM. Alterations in this process could affect the physiological role of HA in the surrounding tissue (Monslow et al 2015). In GO, OFs secrete large amounts of HA in response to, as of now, only partially characterized cytokines and antibodies (Bahn 2010).…”

Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages

“…Due to its hygroscopic and viscoelastic nature, HA can increase hydration in the interstitial matrix of tissues (reviewed in refs 1, 2 and 3). CD44 is present on most cells and is a cell surface receptor for extracellular HA4.…”

Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

“…In many cases HA-protein interactions contribute to stabilization of the matrix and thus tissue homeostasis 3, 4 ; examples include the massive complexes formed between HA and chondroitin sulfate proteoglycans that provide load bearing properties to cartilage, skin and brain via hydration/extension of the chondroitin sulfate chains 1, 2 . However, synthesis of new matrices and matrix remodeling also occurs during certain physiological processes, such as ovulation, as well as in response to tissue injury, inflammation and disease 4–6 .…”

“…In many cases HA-protein interactions contribute to stabilization of the matrix and thus tissue homeostasis 3, 4 ; examples include the massive complexes formed between HA and chondroitin sulfate proteoglycans that provide load bearing properties to cartilage, skin and brain via hydration/extension of the chondroitin sulfate chains 1, 2 . However, synthesis of new matrices and matrix remodeling also occurs during certain physiological processes, such as ovulation, as well as in response to tissue injury, inflammation and disease 4–6 . In these cases, HA along with the sulfated GAGs, chondroitin sulfate (CS; a copolymer of GlcA and N-acetyl galactosamine (GalNAc)) and heparan sulfate (HS; a copolymer of GlcA or iduronic acid (IdoA) and GlcNAc), are known to play a key role in dictating tissue structure, cell fate and availability of extracellular signaling molecules in the extracellular matrix 7–10 .…”