LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells

• Published in: Scientific reports 2019-02, Vol.9 (1), p.2072-2072, Article 2072
• Main Authors: Miyoshi, Masato, Kakinuma, Sei, Kamiya, Akihide, Tsunoda, Tomoyuki, Tsuchiya, Jun, Sato, Ayako, Kaneko, Shun, Nitta, Sayuri, Kawai-Kitahata, Fukiko, Murakawa, Miyako, Itsui, Yasuhiro, Nakagawa, Mina, Azuma, Seishin, Nakauchi, Hiromitsu, Asahina, Yasuhiro, Watanabe, Mamoru
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/31; 13/51; 38/61; 42/44; 631/532/1360; 692/4020/4021/288/2140; Cell culture; Cell interactions; Cell lines; Collagen; Epithelium; Genotype & phenotype; Hepatocytes; Homeobox; Humanities and Social Sciences; Laminin; Liver; Mesenchyme; multidisciplinary; Phenotypes; Pluripotency; Progenitor cells; Rodents; Science; Science (multidisciplinary); Stellate cells; Stem cells; Vitamin A
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-37430-9

Human induced pluripotent stem (iPS) cells can differentiate into hepatocyte lineages, although the phenotype of the differentiated cells is immature compared to adult hepatocytes. Improvement of cell-cell interactions between epithelium and mesenchyme is a potential approach to address this phenotype issue. In this study, we developed a model system for improving interactions between human iPS-derived hepatic progenitor cells (iPS-HPCs) and human iPS-derived hepatic stellate cell-like cells (iPS-HSCs). The phenotype of iPS-HSCs, including gene and protein expression profiles and vitamin A storage, resembled that of hepatic stellate cells. Direct co-culture of iPS-HSCs with iPS-HPCs significantly improved hepatocytic maturation in iPS-HPCs, such as their capacity for albumin production. Next, we generated iPS cell lines overexpressing LIM homeobox 2 (LHX2), which suppresses myofibroblastic changes in HSCs in mice. Hepatocytic maturation in iPS-HPCs was significantly increased in direct co-culture with iPS-HSCs overexpressing LHX2, but not in co-culture with a human hepatic stellate cell line (LX-2) overexpressing LHX2. LHX2 regulated the expression of extracellular matrices, such as laminin and collagen, in iPS-HSCs. In conclusion, this study provides an evidence that LHX2 upregulation in iPS-HSCs promotes hepatocytic maturation of iPS-HPCs, and indicates that genetically modified iPS-HSCs will be of value for research into cell-cell interactions.