Persistent biliary hypoxia and lack of regeneration are key mechanisms in the pathogenesis of posttransplant nonanastomotic strictures

• DOI: 10.1002/hep.32166
• Publication Date: 2021-09-20T18:34:23Z
• Authors: Iris E. M. de Jong; Diletta Overi; Guido Carpino; Annette S. H. Gouw; Marius C. van den...; Léon C. van Kempen; Carmine Mancone; Paolo Onori; Vincenzo Cardinale; Luca Casadei; Domenico Alvaro; Robert J. Porte; Eugenio Gaudio
• Keywords: Hypoxia

Abstract Background and Aims Nonanastomotic biliary strictures (NAS) are a major cause of morbidity after orthotopic liver transplantation (OLT). Although ischemic injury peribiliary glands (PBGs) vascular plexus during OLT has been associated with the later development NAS, exact underlying mechanisms remain unclear. We hypothesized that bile ducts patients NAS suffer from ongoing hypoxia lack regeneration PBG stem/progenitor cells. Approach Results Forty‐two patients, requiring retransplantation for either ( n = 18), hepatic artery thrombosis (HAT; 13), or nonbiliary graft failure (controls; 11), were included in this study. Histomorphological analysis perihilar was performed to assess differences markers cell proliferation differentiation PBGs, microvascular density (MVD), hypoxia. In addition, isolated human tree stem cells (hBTSCs) used examine exo‐metabolomics vitro toward mature cholangiocytes. Bile HAT had significantly reduced indices mass, cellular (mucus production, secretin receptor expression, primary cilia), MVD, increased apoptosis marker compared controls. Metabolomics hBTSCs cholangiocytes revealed switch glycolytic oxidative metabolism, indicating need oxygen. Conclusions characterized by microscopic phenotype chronic attributed loss microvasculature, resulting into These findings suggest persistent is key mechanism OLT.