Adipose-Derived Stem Cells Protect Ischemia-Reperfusion and Partial Hepatectomy by Attenuating Endoplasmic Reticulum Stress.

Zhihui Jiao,Xiaoning Liu,Qianzhen Zhang,Boyang Liu,Yajun Ma,Hongbin Wang,Yansong Ge

doi:10.3389/fcell.2020.00177

Abstract

Ischemia-reperfusion (IR) is an inevitable complication of liver surgery. Recent studies indicate a critical role of endoplasmic reticulum stress (ERS) in hepatic IR. Mesenchymal stem cells (MSCs) have proven to be an effective tool for tissue regeneration and treatment of various diseases, including that of the liver. However, the mechanisms underlying the therapeutic effects of stem cells on hepatic IR injury (IRI) are still poorly understood, especially in the context of ERS. In this study, we established a porcine model of hepatic IRI and partial hepatectomy, and transplanted the animals with adipose-derived mesenchymal stem cells (ADSCs) isolated from miniature pigs. ADSCs not only alleviated the pathological changes in the liver parenchyma following IRI, but also protected the resident hepatocytes from damage. Mechanistically, the ADSCs significantly downregulated ERS-related proteins, including GRP78, p-eIF2α, ATF6 and XBP1s, as well as the proteins involved in ERS-induced apoptosis like p-JNK, ATF4 and CHOP. Taken together, ADSCs can alleviate hepatic IRI by inhibiting ERS and its downstream apoptotic pathways in the hepatocytes, indicating its therapeutic potential in liver diseases.

Highlights

The endoplasmic reticulum (ER) is the site of protein synthesis, post-translational modifications, folding and trafficking
Adipose-derived mesenchymal stem cells are identified on the basis of morphology, immunophenotype and differentiation potential
The adipose-derived mesenchymal stem cells (ADSCs) cultured in osteogenic media for 21 days showed the presence of alizarin red-stained calcium crystals (Figure 2C), and PAS-positive glycogen granules were seen after hepatic differentiation (Figure 2D) for 21 days

Summary

Introduction

The endoplasmic reticulum (ER) is the site of protein synthesis, post-translational modifications, folding and trafficking. It regulates the cellular stress response and calcium levels, apart from synthesizing cholesterol, steroids and other lipids. ER stress (ERS) is characterized by protein misfolding, accumulation of the aberrant proteins and Ca2+ imbalance, which triggers the unfolded protein response (UPR) (Kozutsumi et al, 1988) and the apoptotic pathway. The UPR in mammalian cells is mediated by the PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE-1) pathways, which can trigger apoptosis if severe or sustained ERS damages ER function. UPR can alleviate the ERS and protect cells from apoptosis (Kim et al, 2008), prolonged

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