Tissue-bound hyaluronan molecular weight as a regulator of dendritic cell immune potency

Hyaluronic acid (HA) is a major glycosaminoglycan found in the extracellular matrix (ECM) and exhibits immunoregulatory properties depending on its molecular weight (MW). However, the impact of tissue bound HA on dendritic cell (DC) functions is not well understood due to the varying distribution of HA MW under different physiological and pathological conditions. To investigate DCs in defined biosystems, we used three-dimensional (3D) collagen matrices modified with HA of specific MW, while maintaining similar microstructure and HA levels. Using these matrices, we examined the influence of HA on cytokine binding and observed distinct properties depending on the presence and MW of HA, suggesting modulation of cytokine availability by the different MW of HA. Our studies on DC immune potency revealed that low molecular weight HA (LMW-HA; 8-15 kDa) enhances immature DC (iDC) differentiation and antigen uptake, while medium (MMW-HA; 500-750 kDa) and high molecular weight HA (HMW-HA; 1250-1500 kDa) increase cytokine secretion in matured DCs (mDCs). Interestingly, the modulation of DCs surface marker expression and cytokine secretion by different MW of HA appeared to be independent of CD44. However, we found that cytokine secretion of DCs was dependent on the CD44 receptor regardless of the presence or absence of HA in the matrix. Additionally, we observed reduced migratory capacity of iDCs and mDCs when cultured on MMW- and HMW-HA matrices, and this effect was dependent on CD44. In summary, our findings provide new insights into the MW-dependent effects of tissue-bound HA on DCs, opening avenues for the design of DC-modulating materials to enhance DC-based therapy.