Hyaluronic Acid Stimulated Enterocytic Differentiation of Intestinal Stem Cells and Enhanced Enteroid Grafting on Scaffolds

Hyaluronic acid (HA) is one of the main components of the extracellular matrix, and functions as a stabilizing molecule for cell-niche interactions. Although the mechanism of HA in supporting cell attachment is debatable, HA-based scaffolds are increasingly being applied in tissue engineering owing to their excellent mechanical properties and biocompatibility. HA reportedly enhances the intestinal growth in postnatal mice. In the present study, we aimed to investigate the effects of HA on intestinal stem cells (ISCs) using an in vitro enteroid culture system. A high-concentration of HA (0.5 mg/mL) significantly lowered the proliferative activity of ISCs with decreased enteroid-forming efficiency compared to the control ISCs. In contrast, a low-concentration of HA (0.1 mg/mL) did not affect the enteroid-forming efficiency of ISCs, but up regulated markers of enterocytic differentiation, villin, and HA receptor, CD44 and TLR4, in the enteroid cells. When enteroid fragments were seeded on an intestinal submucosa bioscaffold, HA treatment enhanced the growth and differentiation of enteroid cells on the material with a high villin expression level in the cell grafts. These results suggest that HA treatment is effective in promoting enterocytic differentiation of ISCs and enteroid grafting on scaffolds.