Hyaluronan goes to great length.

Hyaluronan is a major non-protein component of extracellular matrix that affects biomechanical properties of tissues and interacts with cell receptors. Hyaluronan is a linear glycosaminoglycan composed of repeating disaccharides of (β, 1-4)-glucuronic acid (GlcUA) and (β, 1-3)-N-acetyl glucosamine (GlcNAc). The length of hyaluronan can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties. HMW-HA is used in the clinic to treat arthritis, and as a filler in surgery and in the form of rinses to treat local inflammation. However, HMW-HA products used in the clinic come in a range of sizes between 0.5-6 mDa that are used interchangeably. Remarkably, the tissues of a long-lived and cancer-resistant rodent, the naked mole rat, contain abundant HA of very high molecular weight. While human fibroblasts secrete HA up to 2 MDa, naked mole rat fibroblasts produce HA of 6-12 MDa. Does this very high HMW-HA (vHMW-HA) differ functionally from HMW-HA? We found that vHMW-HA has superior cytoprotective properties compared to HMW-HA, and interacts differently with the CD44 receptor leading to distinct transcriptional changes (Takasugi et al. (2020), Nat Commun). These results indicate that vHMW-HA has greater therapeutic benefits than the standard HMW-HA.