Interaction between hyaluronan and hyaluronan-mediated motility receptor affects telomere maintenance in skin fibroblasts with Hutchinson-Gilford progeria syndrome

Summary: Abstract Body: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic and premature aging disorder characterized by shortened telomeres, leading to significant skin changes, including loss of elasticity, wrinkling, depigmentation, and extracellular matrix (ECM) disruption. Currently, treatment options for HGPS are limited. Hence, we aimed to explore a novel approach to manage HGPS by regulating telomere shortening through manipulating cell-matrix interactions. Hyaluronan is a vital viscoelastic polysaccharide in the skin's ECM that maintains skin elasticity, integrity, and moisture. Its metabolism is significantly altered during aging and is implicated in HGPS. We demonstrated that growth factors and transcription factors differentially regulate hyaluronan synthases in skin cells, contributing to aging. Furthermore, we found that the matrix hyaluronan modulates telomerase reverse transcriptase transcription in cancer cells, depending on its molecular weight. The hyaluronan-mediated motility receptor (HMMR), an oncogene, is unconventionally exported to the cell surface and binds to hyaluronan under stress. We observed that HMMR enhances telomerase-mediated telomere elongation in mice, prompting us to explore HMMR's role in regulating telomere length in HGPS. Upon eliminating HMMR and its natural antisense long noncoding RNA HMMR-AS1 in primary HGPS skin fibroblasts, we observed a suppression of p21 and p16INK4a mRNA expression (p<0.05), indicating HMMR's role in regulating senescence and telomere shortening in HGPS. Culturing HGPS skin fibroblasts in two ECM-mimetic hydrogels revealed that the hybrid hydrogel (low + high molecular weight hyaluronan) increased HMMR expression. In contrast, the low molecular weight hydrogel suppressed it (p<0.05). These results highlight the significance of hyaluronan-HMMR interaction in telomere maintenance in HGPS, positioning HMMR as a potential biomarker for aging and a likely target for HGPS therapy. Kaustuv Basu¹, Luc Mongeau¹ 1. Department of Mechanical Engineering, McGill University, Montreal, QC, Canada. Cell Communication Networks and Stromal Biology