Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Transplantation. 2023 Jun 1;107(6):e161-e172. doi: 10.1097/TP.0000000000004531. Epub 2023 May 23.
End-ischemic ex situ normothermic machine perfusion (NMP) enables assessment of donor livers prior to transplantation. The objective of this study was to provide support for bile composition as a marker of biliary viability and to investigate whether bile ducts of high-risk human donor livers already undergo repair during NMP.
Forty-two livers that were initially declined for transplantation were included in our NMP clinical trial. After NMP, livers were either secondary declined (n = 17) or accepted for transplantation (n = 25) based on the chemical composition of bile and perfusate samples. Bile duct biopsies were taken before and after NMP and assessed using an established histological injury severity scoring system and a comprehensive immunohistochemical assessment focusing on peribiliary glands (PBGs), vascular damage, and regeneration.
Bile ducts of livers that were transplanted after viability testing during NMP showed better preservation of PBGs, (micro)vasculature, and increased cholangiocyte proliferation, compared with declined livers. Biliary bicarbonate, glucose, and pH were confirmed as accurate biomarkers of bile duct vitality. In addition, we found evidence of PBG-based progenitor cell differentiation toward mature cholangiocytes during NMP.
Favorable bile chemistry during NMP correlates well with better-preserved biliary microvasculature and PBGs, with a preserved capacity for biliary regeneration. During NMP, biliary tree progenitor cells start to differentiate toward mature cholangiocytes, facilitating restoration of the ischemically damaged surface epithelium.
缺血后体外常温机器灌注（NMP）使供体肝脏在移植前可以进行评估。本研究的目的是为胆汁成分作为胆汁活力的标志物提供支持，并研究高危人类供体肝脏的胆管是否已经在 NMP 过程中开始修复。
我们的 NMP 临床试验纳入了 42 例最初因移植而被拒绝的肝脏。NMP 后，根据胆汁和灌注液样本的化学成分，将肝脏分为次要拒绝（n=17）或接受移植（n=25）。在 NMP 前后采集胆管活检，并使用既定的组织学损伤严重程度评分系统和全面的免疫组织化学评估，重点评估周围胆管（PBGs）、血管损伤和再生。
在 NMP 期间进行生存能力测试后接受移植的肝脏的胆管与被拒绝的肝脏相比，PBGs、（微）血管和胆管细胞增殖得到更好的保留。胆汁碳酸氢盐、葡萄糖和 pH 值被确认为胆管活力的准确生物标志物。此外，我们发现在 NMP 过程中存在 PBG 源性祖细胞向成熟胆管细胞分化的证据。
NMP 期间良好的胆汁化学性质与更好保存的胆管微血管和 PBGs 以及保存的胆管再生能力密切相关。在 NMP 期间，胆管树祖细胞开始向成熟的胆管细胞分化，有助于修复缺血性损伤的表面上皮。
