PDF(Pubmed)
Abstract：
Premature senescence occurs in adult hepatobiliary diseases and worsens the prognosis through deleterious liver remodeling and hepatic dysfunction. Senescence might also arises in biliary atresia (BA), the first cause of pediatric liver transplantation. Since alternatives to transplantation are needed, our aim was to investigate premature senescence in BA and to assess senotherapies in a preclinical model of biliary cirrhosis.
BA liver tissues were prospectively obtained at hepatoportoenterostomy (n=5) and liver transplantation (n=30) and compared to controls (n=10). Senescence was investigated through spatial whole transcriptome analysis, SA-β-gal activity, p16 and p21 expression, γ-H2AX and senescence-associated secretory phenotype (SASP). Human allogenic liver-derived progenitor cells (HALPC) or dasatinib and quercetin (D+Q) were administrated to two-month-old Wistar rats after bile duct ligation (BDL).
Advanced premature senescence was evidenced in BA livers from early stage and continued to progress until liver transplantation. Senescence and SASP were predominant in cholangiocytes, but also present in surrounding hepatocytes. HALPC but not D+Q reduced the early marker of senescence p21 in BDL rats and improved biliary injury (serum γGT and Sox9 expression) and hepatocytes mass loss (Hnf4a).
BA livers displayed advanced cellular senescence at diagnosis that continued to progress until liver transplantation. HALPC reduced early senescence and improved liver disease in a preclinical model of BA, providing encouraging preliminary results regarding the use of senotherapies in pediatric biliary cirrhosis.
BA liver tissues were prospectively obtained at hepatoportoenterostomy (n=5) and liver transplantation (n=30) and compared to controls (n=10). Senescence was investigated through spatial whole transcriptome analysis, SA-β-gal activity, p16 and p21 expression, γ-H2AX and senescence-associated secretory phenotype (SASP). Human allogenic liver-derived progenitor cells (HALPC) or dasatinib and quercetin (D+Q) were administrated to two-month-old Wistar rats after bile duct ligation (BDL).
Advanced premature senescence was evidenced in BA livers from early stage and continued to progress until liver transplantation. Senescence and SASP were predominant in cholangiocytes, but also present in surrounding hepatocytes. HALPC but not D+Q reduced the early marker of senescence p21 in BDL rats and improved biliary injury (serum γGT and Sox9 expression) and hepatocytes mass loss (Hnf4a).
BA livers displayed advanced cellular senescence at diagnosis that continued to progress until liver transplantation. HALPC reduced early senescence and improved liver disease in a preclinical model of BA, providing encouraging preliminary results regarding the use of senotherapies in pediatric biliary cirrhosis.
摘要：
背景：早衰发生在成人肝胆疾病中，并通过有害的肝重塑和肝功能障碍使预后恶化。衰老也可能出现在胆道闭锁（BA），小儿肝移植的第一个原因。由于需要移植的替代方法，我们的目的是研究BA的过早衰老,并评估胆汁性肝硬化临床前模型中的衰老疗法.
方法：在肝肠造口术（n=5）和肝移植（n=30）中前瞻性获得BA肝组织，并与对照组（n=10）进行比较。通过空间全转录组分析研究衰老，SA-β-gal活性，p16和p21表达，γ-H2AX和衰老相关分泌表型(SASP)。在胆管结扎（BDL）后，将人同种异体肝源性祖细胞（HALPC）或达沙替尼和槲皮素（DQ）给予两个月大的Wistar大鼠。
结果：从早期开始，BA肝脏出现晚期早衰，并持续进展直至肝移植。胆管细胞以衰老和SASP为主，但也存在于周围的肝细胞中。HALPC而不是DQ降低了BDL大鼠衰老p21的早期标志物，并改善了胆道损伤（血清γGT和Sox9表达）和肝细胞质量损失（Hnf4a）。
结论：BA肝脏在诊断时表现出晚期细胞衰老，并持续进展直至肝移植。在BA的临床前模型中，HALPC减少了早期衰老并改善了肝脏疾病，提供了有关儿科胆汁性肝硬化中使用营养疗法的令人鼓舞的初步结果。
方法：在肝肠造口术（n=5）和肝移植（n=30）中前瞻性获得BA肝组织，并与对照组（n=10）进行比较。通过空间全转录组分析研究衰老，SA-β-gal活性，p16和p21表达，γ-H2AX和衰老相关分泌表型(SASP)。在胆管结扎（BDL）后，将人同种异体肝源性祖细胞（HALPC）或达沙替尼和槲皮素（DQ）给予两个月大的Wistar大鼠。
结果：从早期开始，BA肝脏出现晚期早衰，并持续进展直至肝移植。胆管细胞以衰老和SASP为主，但也存在于周围的肝细胞中。HALPC而不是DQ降低了BDL大鼠衰老p21的早期标志物，并改善了胆道损伤（血清γGT和Sox9表达）和肝细胞质量损失（Hnf4a）。
结论：BA肝脏在诊断时表现出晚期细胞衰老，并持续进展直至肝移植。在BA的临床前模型中，HALPC减少了早期衰老并改善了肝脏疾病，提供了有关儿科胆汁性肝硬化中使用营养疗法的令人鼓舞的初步结果。
