Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA.
Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA.
Hepatology. 2019 Jun;69(6):2586-2597. doi: 10.1002/hep.30550. Epub 2019 Apr 11.
In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1 , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1 cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-β6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) β activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.
在胆道闭锁（BA）患者中，肝内胆管纤维化的程度与先天性胆管病的成功手术旁路以及随后的无移植生存呈负相关。我们最近将一群表达 prominin-1（Prom1）的肝祖细胞的扩张与胆管纤维化联系起来。在此，我们假设 Prom1 表达的祖细胞在 BA 相关纤维化中起作用。在新生小鼠中诱导恒河猴轮状病毒（RRV）介导的实验性 BA，这些小鼠纯合了位于 Prom1 基因座的 Prom1 转基因，从而产生功能性 Prom1 敲除（KO）小鼠及其野生型（WT）同窝仔鼠。分析了来自儿童肝脏疾病研究联合会的 BA 婴儿的临床数据和组织样本。WT 和 KO 小鼠均存在肝外胆管闭塞；血清总胆红素（TBili）水平无差异。在 RRV 诱导的 BA 中通常观察到的 PROM1 细胞群体在 KO 小鼠中的肝内门管区扩张不存在。与 WT 相比，RRV 处理的 KO 小鼠表现出明显更少的细胞角蛋白 19（CK19）阳性胆管反应（P = 0.0004）和明显更少的门管区胶原沉积（P = 0.0001）。与 WT 相比，RRV 处理的 KO 小鼠表达的整合素-β6 明显减少，整合素-β6 编码转化生长因子（TGF）β激活物的一个关键胆管特异性亚基（P = 0.0004）。在术后 3 个月内 TBili≤1.5mg/dL 的胆道引流成功（高度预测无移植生存增加）的婴儿中，与 TBili>1.5 的婴儿相比，肝 PROM1、CK19 和 COLLAGEN-1α 的表达明显减少（P<0.05）。结论：Prom1 通过整合素介导的 TGF 途径激活在胆管纤维化中起重要作用。
