Biotechnology and Bioprocess Engineering 2023; 28(3): 451-458  
Hyaluronic Acid Stimulated Enterocytic Differentiation of Intestinal Stem Cells and Enhanced Enteroid Grafting on Scaffolds
Siu Chung Ha, Ya-Hui Tsai, Shinn-Gwo Hong, Yun Chen, and Chao-Ling Yao
Siu Chung Ha, Yun Chen*
Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei 220, Taiwan
Tel: +886-2-89667000 ext.1659; Fax: +886-2-89674263
Siu Chung Ha, Ya-Hui Tsai, Shinn-Gwo Hong, Chao-Ling Yao
Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan 320, Taiwan
Yun Chen
Graduate Institute of Medicine, Yuan Ze University, Chung-Li, Taoyuan
320, Taiwan
Chao-Ling Yao*
Department of Chemical Engineering, National Cheng Kung University, East Dist., Tainan 701, Taiwan
Tel: +886-6-2757575; Fax: +886-6-2344496
Siu Chung Ha and Ya-Hui Tsai contributed equally to this work.
Received: September 2, 2022; Revised: December 25, 2022; Accepted: February 7, 2023; Published online: June 30, 2023.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: hyaluronic acid, intestinal stem cell, enteroid, intestinal tissue engineering

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