Therapy with adipose tissue-derived stem cells ameliorated the NASH cirrhosis by attenuating ER stress in hepatocyte involving hepatic stellate cells.

[Background] We have elucidated the efficacy of adipose tissude-derived stem cells (ADSCs) therapy for NASH cirrhosis. As for NASH pathogenesis, the multiple pathways, including the endoplasmic reticulum (ER) stress, were reported. In this study, we investigated details of ER stress in the NASH progression and therapeutic mechanisms of ADSCs. [Methods] ADSCs, isolated from murine inguinal adipose tissue, were injected into splenic subcapsular of NASH mice on weeks 8 and 10, and liver tissues were obtained on week 12 to analyze gene expression, protein expression, and apoptosis. H2.35 and IMS/N, which were murine hepatocyte and stellate cell lines, respectively, were co-cultured with ADSCs in the medium containing the palmitic acid (PA) to analyze protein and gene expression.
[Results] In the liver of NASH mice, the expression of the Perk molecule, which is induced by ER stress and conducts to apoptosis, was enhanced. ADSCs treatment attenuated the Perk expression and apoptotic cells in the liver of NASH mice. The PA and the IMS/N-cultured media collaboratively enhanced the Perk expression of H2.35. However, the media from IMS/N, co-cultured with MSCs, did not enhance the Perk expression of H2.35. Microarray analysis showed that the co-cultured with MSCs attenuated the inflammatory cytokine-related pathways, including TNF-alpha, IFN-gamma, and IL-1b. [Conclusion] ADSCs therapy ameliorated NASH cirrhosis, by attenuating hepatocytes’ ER stress via hepatic stellate cells.