Human liver organoids to predict the outcome of Kasai portoenterostomy [Oral presentation]

Abstract

<p><strong>Purpose</strong> </p><p>This study investigated the prognostic utility of patient-derived liver organoids after Kasai portoenterostomy (KPE). </p><p><strong>Method</strong> </p><p>Liver biopsies from biliary atresia (BA) patients during and after KPE were used to generate organoids for RNA-sequencing analysis. Control organoids were derived from non-BA control livers. Differential gene expression and Gene Set Variation analyses were performed to assess post-KPE transcriptomic changes between native liver survivors (NLS) and liver transplant recipients (LTR).</p><p><strong>Results</strong> </p><p>We generated robust organoid datasets: 63 from liver biopsies during KPE (9 patients), 106 from post-KPE livers (12 livers; 11 patients), and 48 from control livers (9 patients). During KPE, BA organoids displayed robust hepatocyte expression, a trait notably reduced in control organoids. Notably, post-KPE NLS organoids revealed a significant decrease in hepatocyte expression features and a general increase in cholangiocyte expression features. A similar hepatocyte-to-cholangiocyte expression transition was evidenced in a unique case with both during and post-KPE organoids from the same NLS patient. In contrast, post-KPE LTR-derived organoids maintained a high level of hepatocyte expression features, a trend also seen in an LTR patient with both during and post-KPE organoids. These findings, from both the collective organoid dataset and individual patient samples, reinforce KPE’s potential to facilitate hepatocyte-to-cholangiocyte expression reversal.</p><p><strong>Conclusion</strong> </p><p>Elevated expression of hepatocyte features in KPE organoids may indicate aberrant cholangiocyte development in BA livers. The hepatocyte-to-cholangiocyte expression transition observed in NLS post-KPE could suggest proper cholangiocyte development and a successful KPE with a good prognosis. Conversely, the absence of such a shift after KPE corroborates the failure to ameliorate BA disease progression.</p>