Jiao Zhihui, Liu Xiaoning, Ma Yajun, Ge Yansong, Zhang Qianzhen, Liu Boyang, Wang Hongbin
College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, China.
Front Cell Dev Biol. 2020 Mar 20;8:177. doi: 10.3389/fcell.2020.00177. eCollection 2020.
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.
缺血再灌注（IR）是肝脏手术不可避免的并发症。最近的研究表明内质网应激（ERS）在肝脏IR中起关键作用。间充质干细胞（MSCs）已被证明是组织再生和治疗包括肝脏疾病在内的各种疾病的有效工具。然而，干细胞对肝脏IR损伤（IRI）治疗作用的潜在机制仍知之甚少，尤其是在ERS背景下。在本研究中，我们建立了猪肝脏IRI和部分肝切除术模型，并将从微型猪分离的脂肪来源间充质干细胞（ADSCs）移植到动物体内。ADSCs不仅减轻了IRI后肝实质的病理变化，还保护了驻留肝细胞免受损伤。从机制上讲，ADSCs显著下调了ERS相关蛋白，包括GRP78、p-eIF2α、ATF6和XBP1s，以及参与ERS诱导凋亡的蛋白，如p-JNK、ATF4和CHOP。综上所述，ADSCs可通过抑制肝细胞中的ERS及其下游凋亡途径来减轻肝脏IRI，表明其在肝脏疾病中的治疗潜力。
