Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice

Kosuke Ishida, Akihiro Seki, Kazunori Kawaguchi, Alessandro Nasti, Masatoshi Yamato, Hiiro Inui, Takuya Komura, Taro Yamashita, Kuniaki Arai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda, Takashi Wada, Kenichi Harada, Shuichi Kaneko, Yoshio Sakai

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Adipose tissue-derived stem cells (ADSCs) have been suggested as a novel treatment for non-alcoholic steatohepatitis (NASH); however, the mechanisms underlying their therapeutic effect remain poorly understood. In this study, we aimed to investigate the association of Notch signaling, which is crucial for cellular proliferation and differentiation in ADSC-mediated treatment of NASH. Flow cytometry analysis of ADSCs showed that they expressed the Notch ligands JAG1, DLL1, and DLL4. The expression of genes associated with the Notch signaling pathway was attenuated in hepatocytes of NASH model mice. We further observed ADSC-mediated activation of Notch signaling in these hepatocytes in addition to an increase in proliferating cell nuclear antigen+ cells and a decrease in TdT-mediated dUTP-biotin nick end labeling+ apoptotic cells. Co-culture of palmitic acid-induced steatotic hepatocytes and ADSCs resulted in the activation of Notch signaling and reduction of apoptosis of steatotic hepatocytes. Moreover, inhibition of Notch signaling by a γ-secretase inhibitor and knockdown of Notch ligands using siRNA attenuated the anti-apoptotic effect of co-cultured ADSCs in vitro. Our findings show that the Notch signaling pathway is involved in the inhibition of apoptosis and restoration of cellular proliferation of hepatocytes from NASH mice following ADSC treatment.

Original languageEnglish
Article number102425
JournalStem Cell Research
Volume54
DOIs
StatePublished - Jul 2021
Externally publishedYes

Keywords

  • Adipose tissue-derived stem cells
  • Apoptosis
  • Non-alcoholic steatohepatitis
  • Notch

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