Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties

Abstract

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stressinduced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.

Hyaluronic Acid: The Influence of Molecular Weight on Structural, Physical, Physico-Chemical, and Degradable Properties of Biopolymer

“…It has previously been suggested that HA of different MW may affect the same receptors differently; however, recent study refutes this theory [ 23 ]. On the other hand, it has been shown that HA of very high molecular weight (6000 kDa) produced by naked mole-rat suppresses the signaling of CD44, which results in altered expression of a subset of p53 target genes, thereby suggesting that HMWHA has the properties of a cytoprotective molecule [ 24 ], but there are differences in the genes regulated by p53 between different species so this investigation is restricted to human cells.…”

Epidermal stem cell compartment remains unaffected through aging in naked mole-rats

“…S6C). Masson’s trichrome staining for collagenous connective tissue fibers revealed no difference between the 2 groups just like hyaluronic acid, a linear polysaccharide of the extracellular matrix contributing to contact inhibition and cell proliferation( 41 ) (Fig. 5 D-E).…”

Naked mole‐rats are extremely resistant to post‐traumatic osteoarthritis

“…Reduced senescence in NMR joints may be another factor protecting from OA. As HMW-HA has cytoprotective properties (Takasugi et al, 2020), it may be acting to attenuate senescence.…”

“…Reduced senescence in NMR joints may be another factor protecting from OA. As HMW‐HA has cytoprotective properties (Takasugi et al, 2020), it may be acting to attenuate senescence. Finally, there may be systemic factors contributing to NMR OA resistance, such as lower levels of inflammatory response, as high molecular weight HA downregulates inflammation (Petrey & de la Motte, 2014).…”