Identification of the small molecule compound which induces hepatic differentiation of human mesenchymal stem cells

Noriko Itaba; Tomohiko Sakabe; Keita Kanki; Junya Azumi; Hiroki Shimizu; Yohei Kono; Yoshiaki Matsumi; Ken-Ichiro Abe; Takayuki Tonoi; Hiroyuki Oka; Toshihiko Sakurai; Hiroyuki Saimoto; Minoru Morimoto; Yo Mabuchi; Yumi Matsuzaki; Goshi Shiota

doi:10.1016/j.reth.2015.10.001

Identification of the small molecule compound which induces hepatic differentiation of human mesenchymal stem cells

Regen Ther. 2015 Nov 26:2:32-41. doi: 10.1016/j.reth.2015.10.001. eCollection 2015 Dec.

Authors

Affiliations

¹ Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
² Research Center for Bioscience and Technology, Tottori University, 4-101, Koyama, Tottori 680-8550, Japan.
³ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan.
⁴ Department of Biochemistry and Biophysics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
⁵ Department of Life Science, Laboratory of Tumor Biology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.

Abstract

Human mesenchymal stem cells (MSCs) are expected to have utility as a cell source in regenerative medicine. Because we previously reported that suppression of the Wnt/β-catenin signal enhances hepatic differentiation of human MSCs, we synthesized twenty-three derivatives of small molecule compounds originally reported to suppress the Wnt/β-catenin signal in human colorectal cancer cells. We then screened these compounds for their ability to induce hepatic differentiation of human UE7T-13 MSCs. After screening using WST assay, TCF reporter assay, and albumin mRNA expression, IC-2, a derivative of ICG-001, was identified as a potent inducer of hepatic differentiation of human MSCs. IC-2 potently induced the expression of albumin, complement C3, tryptophan 2,3-dioxygenase (TDO2), EpCAM, C/EBPα, glycogen storage, and urea production. Furthermore, we examined the effects of IC-2 on human bone marrow mononuclear cell fractions sorted according to CD90 and CD271 expression. Consequently, CD90⁺ CD271⁺ cells were found to induce the highest production of urea and glycogen, important hepatocyte functions, in response to IC-2 treatment. CD90⁺ CD271⁺ cells also highly expressed albumin mRNA. As the CD90⁺ CD271⁺ population has been reported to contain a rich fraction of MSCs, IC-2 apparently represents a potent inducer of hepatic differentiation of human MSCs.

Keywords: Hepatic differentiation; Mesenchymal stem cells; Small molecule compound; Wnt/β-catenin signal inhibitor.