Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cell Metab. 2019 Aug 6;30(2):385-401.e9. doi: 10.1016/j.cmet.2019.06.017.
The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.
肝脂肪变性进展为非酒精性脂肪性肝炎和终末期肝病的机制仍不清楚。SIRT1 控制的肝细胞代谢紊乱在近交系动物的脂肪肝发展中起作用。由于人类遗传变异性的限制，使用人类组织进行类似研究的能力受到限制。我们生成了具有可控 SIRT1 表达的人诱导多能干细胞 (iPSC)。通过将编辑的 iPSC 分化为肝细胞并敲低 SIRT1，我们发现脂肪酸生物合成增加，加剧了脂肪堆积。为了模拟人类脂肪肝，我们用人间质细胞、成纤维细胞、巨噬细胞和人 SIRT1 敲低 iPSC 衍生的肝细胞重新填充去细胞化的大鼠肝脏，发现人 iPSC 衍生的肝组织发生大脂变，获得促炎表型，并与人脂肪肝具有相似的脂质和代谢特征。基因编辑的人肝组织的生物制造可能成为研究人类肝脏生物学和疾病的重要工具。
