低分子化合物を用いた肝前駆細胞による非アルコール性脂肪性肝炎の改善

Background Can Background be changed from bold to normal text?: Chemically-induced liver progenitors (CLiPs) have promising applications in liver regenerative medicine. We aimed to clarify the efficacy of CLiPs for ameliorating fibrosis in a diet-induced nonalcoholic steatohepatitis rat model, since nonalcoholic fatty liver disease is currently recognized as the most common form of chronic liver disease in developed countries. Methods: Primary mature hepatocytes were isolated from 7-week-old male Wistar rats. To establish CLiPs, isolated hepatocytes were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). As an animal model that reproduces NASH pathophysiology, 6-week-old severe combined immunodeficient (SCID) mice were carefully selected and prepared and fed with choline-deficient, L-amino acid-defined, high-fat diet (HFD). After 12 weeks’ HFD feeding, the mice were assigned to continue HFD with or without the administration of rat CLiPs (HFD þ CLiPs and HFD-CLiPs, respectively). Rat CLiPs were administered from the spleen. Hepatic fibrosis was semiquantitatively evaluated according to histology. Liver parenchyma and blood samples were collected for biochemical analyses. Results: Rat CLiPs were positive for CK19 and EpCAM were successfully delivered to the liver. At 8 weeks after CLiPs transplantation, the HFD þ CLiPs group showed significantly less positive staining than the HFD-CLiPs group. Alanine aminotransferase significantly improved in the HFD þ CLiPs group, as demonstrated by Azan staining and aSMA immunostaining. RT qPCR showed that the liver expression of MMP2 and 9 tended to be higher in the HFD þ CLiPs group. Conclusions: The antifibrotic effect of CLiPs was demonstrated in the immunodeficient NASH animal model and may have therapeutic applications in humans.
長崎大学学位論文 学位記番号:博(医歯薬)甲第1508号 学位授与年月日:令和5年3月20日
Author: Shunsuke Murakami, Akihiko Soyama, Daisuke Miyamoto, Takanobu Hara, Kunihito Matsuguma, Hajime Imamura, Hajime Matsushima, Takayuki Tanaka, Yasuhiro Maruya, Tomohiko Adachi, Satoshi Miuma, Masaaki Hidaka, Kengo Kanetaka, Takahiro Ochiya, Susumu Eguchi
Citation: Regenerative Therapy, 21, pp. 574-583; 2022