Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6.

Giusy Sammarco,Luciana Petti,Silvia Restelli,Mohammad Shalaby,Federica Ungaro,Silvia D’Alessio,Gionata Fiorino,Giulia Roda,Vincenzo Arena,Sudharshan Elangovan,Anthony J Day,Stefania Vetrano

doi:10.3390/cells8091074

Abstract

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis.

Highlights

Hyaluronan (HA) is a nonsulfated unbranched polysaccharide composed entirely of a repeating disaccharide of glucuronic acid (GlcA) and N-acetyl-glucosamine (GlcNAc) [1]
The Disease Activity Index (DAI), calculated based on weight changes, bleeding, and the consistency of stools, which reflects the severity of the colitis, did not reveal significant differences between the HA and saline groups (Figure 1B)
The long-term response to drug treatment is less than 50%, and all existing drugs are associated with potential toxicity and systemic effects [17,19]

Summary

Introduction

Hyaluronan (HA) is a nonsulfated unbranched polysaccharide composed entirely of a repeating disaccharide of glucuronic acid (GlcA) and N-acetyl-glucosamine (GlcNAc) [1]. ~10 MDa, and has a broad range of biological activities in mammalian tissues [3]. It is a ubiquitous component of the extracellular matrix (ECM), with a key role in tissue homeostasis, and is required for development, reproductive biology, and immune functions, exerting both structural and signaling activities [4,5]. The control of HA synthesis is, critical in ECM and cell biology. High molecular weight hyaluronan (HMW-HA) suppresses the immune response acting as an anti-inflammatory molecule, acts as an anti-angiogenic factor, and exerts numerous receptor-mediated effects on cell adhesion, migration, mitosis, and inflammation [6].

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