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.
Highlights
In the 80 years that have passed since hyaluronan (HA - known as hyaluronic acid or hyaluronate) was first isolated and purified from the vitreous humor of the eye [1], the perception of this structurally seemingly simple molecule has changed dramatically
Nor have many of the reports where exogenous HA was added, elucidated how this effected the size distribution of endogenous HA, and over time, its effects on tissue architecture and cellular signaling that translate to either recovery of homeostasis or progression of disease. This is especially important in the context of cancer progression, as the effects of altering HA MW may have varying and opposing effects depending on the origin of the cancer, the tissue in which it resides, and the stage of the disease [20]
Low molecular weight–MMW-HA has been reported to facilitate the differentiation of many mesenchymal cells that are activated as a normal response following injury, including chondrocytes [146], fibroblasts [together with their expression of growth factors FGF-2 and KGF [147]], keratinocytes [148], and vascular smooth muscle cell (VSMC)
Summary
E (2015) Hyaluronan – a functional and structural sweet spot in the tissue microenvironment. Transition from homeostatic to reactive matrix remodeling is a fundamental adaptive tissue response to injury, inflammatory disease, fibrosis, and cancer. 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. The impact of matrix organization on inflammation and immunity in particular and the consequent effects on tissue healing and disease outcome are arguably understudied aspects of adaptive stress responses. We review how the predominant glycosaminoglycan hyaluronan (HA) contributes to the structure and function of the tissue microenvironment. We discuss how HA fragmentation impacts restoration of normal tissue function and pathological outcomes in disease
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