Department of Surgery, The University of Hong Kong, Hong Kong SAR, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, China.
Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong SAR, China.
Theranostics. 2017 Oct 24;7(19):4879-4893. doi: 10.7150/thno.20085. eCollection 2017.
Expanded donor criteria poses increased risk for late phase complications such as fibrosis that lead to graft dysfunction in liver transplantation. There remains a need to elucidate the precise mechanisms of post-transplant liver damage in order to improve the long-term outcomes of marginal liver grafts. In this study, we aimed to examine the role of oval cells in fibrogenic development of marginal liver grafts and explore the underlying mechanisms. : Using an orthotopic rat liver transplantation model and human post-transplant liver biopsy tissues, the dynamics of oval cells in marginal liver grafts was evaluated by the platform integrating immuno-labeling techniques and ultrastructure examination. Underlying mechanisms were further explored in oval cells and an Aldose reductase (AR) knockout mouse model simulating marginal graft injury. We demonstrated that activation of aldose reductase initiated oval cell proliferation in small-for-size fatty grafts during ductular reaction at the early phase after transplantation. These proliferative oval cells subsequently showed prevailing biliary differentiation and exhibited features of mesenchymal transition including dynamically co-expressing epithelial and mesenchymal markers, developing microstructures for extra-cellular matrix degradation (podosomes) or cell migration (filopodia and blebs), and acquiring the capacity in collagen production. Mechanistic studies further indicated that transition of oval cell-derived biliary cells toward mesenchymal phenotype ensued fibrogenesis in marginal grafts under the regulation of notch signaling pathway. Oval cell activation and their subsequent lineage commitment contribute to post-transplant fibrogenesis of small-for-size fatty liver grafts. Interventions targeting oval cell dynamics may serve as potential strategies to refine current clinical management.
扩大供者标准会增加晚期并发症的风险,如纤维化,导致肝移植后移植物功能障碍。为了改善边缘供肝的长期预后,仍有必要阐明移植后肝损伤的确切机制。在这项研究中,我们旨在研究卵圆细胞在边缘肝移植物纤维化发展中的作用,并探讨其潜在机制。:我们使用原位大鼠肝移植模型和人移植后肝活检组织,通过整合免疫标记技术和超微结构检查的平台,评估边缘肝移植物中卵圆细胞的动态变化。在卵圆细胞和模拟边缘移植物损伤的醛糖还原酶(AR)敲除小鼠模型中进一步探讨了潜在机制。我们表明,醛糖还原酶的激活在移植后早期小管反应期间引发小体积脂肪移植物中卵圆细胞的增殖。这些增殖的卵圆细胞随后表现出明显的胆管分化,并表现出间充质转化的特征,包括动态共表达上皮和间充质标志物、形成细胞外基质降解(足突)或细胞迁移(微丝和小泡)的微结构,并获得胶原产生的能力。机制研究进一步表明,在 Notch 信号通路的调节下,卵圆细胞衍生的胆管细胞向间充质表型的转变导致边缘移植物中的纤维化。卵圆细胞的激活及其随后的谱系定向有助于小体积脂肪性肝移植物移植后的纤维化。针对卵圆细胞动力学的干预措施可能成为改善当前临床管理的潜在策略。