Healthy peribiliary glands are necessary for successful liver transplantation
Authors: Heather Francis, Debjyoti Kundu, Leonardo Baiocchi
Journal: Hepatology (2022)

Orthotopic liver transplantation (OLT) represents the only definitive cure for end‐stage liver diseases. When the procedure is successful, patient outcome appears nearly miraculous with recovery of general well‐being and physical performance[1]; however, several short‐ and long‐term complications may occur after transplant.[2] Biliary tract complications are frequent after OLT, accounting for ~30% of cases, with leaks and anastomotic and nonanastomotic strictures (NAS) among the most frequent complications.[3] Whereas in the case of anastomotic complications a suboptimal surgical procedure may be generally advocated, the process occurring in NAS remains less clear and is a largely unpredictable condition that causes significant morbidity and graft loss. NAS is thought to occur mainly after enhanced ischemia‐reperfusion injury (IRI); however, it is also associated with transplant in primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) patients.[4] An accumulation of clinical evidence suggests that significant biliary loss is typically observed early after OLT because of IRI; however, NAS develops in a minority of cases.[5] CURRENT STUDY AND FINDINGS In order to clarify the possible path leading from OLT‐associated biliary damage to NAS, de Jong et al. performed a detailed immune‐histological, molecular, and metabolomic study in explanted human NAS livers.[6] In this elegant study, several elements converge in identifying not only IRI, but also chronic ischemia and impaired biliary cell replacement as important elements in the onset of NAS. In fact, peribiliary glands (PBGs),[7] the vital reservoir for biliary cell (i.e., cholangiocyte) reproduction from biliary tree stem/progenitor cells (BTSCs), underwent a relevant disruption and depletion in patients with OLT‐related NAS. Specifically, in 18 livers from patients with OLT‐related NAS, PBG mass was reduced to one half in comparison with control, and these glands exhibited cells with: (1) decreased staining for proliferation markers and (2) increased apoptosis, whereas the expression of cellular senescence markers remained unchanged. Characterization of BTSCs (SRY‐box transcription factor 9 positive) in NAS livers, with regard to their evolution toward a cholangiocyte phenotype (evaluated by expression of secretin receptor and primary cilia formation), demonstrated an impaired progression to mature biliary cells compared to control. The NAS‐affected biliary tract also exhibited increased wall thickness for collagen deposition that was associated with myofibroblast activation. Finally, peribiliary vascular plexus (PVP; the delicate system of interconnecting small vessels surrounding the biliary tree originating from the hepatic artery and allowing for blood flow toward the sinusoidal space) representation was impaired and reduced in the NAS‐affected biliary tract with increased apoptosis of endothelial cells and enhanced expression of ischemia markers such as hypoxia‐inducible factor 1α. Interestingly, investigators from the same group, using bile duct slices of human liver discarded from OLT, previously demonstrated that enhanced proliferative activities in PBGs were effective in restoring the denudated biliary tract with normal cholangiocytes.[8] A schematic provided in Figure 1 depicts the fate of peribiliary glands following IRI and PVP damage.FIGURE 1: Schematic representation of the proposed pathological model leading to nonanastomotic biliary stricture after liver transplant. Created with BioRender.comIn support of these findings, PBG alterations are also present in patients with PSC, a well‐known ductopenic, scarring disorder of the biliary tract.[9] Also in PSC, enhanced PBG cells hyperplasia was observed, supporting the possible evolution toward dysplastic transformation and epithelial‐to‐mesenchymal transition (EMT), thereby sustaining the fibrotic process in the biliary system.[9] Taken together, these studies on PBGs shed light on the important role of these glands in human cholangiopathies. Research focusing on this aspect will likely provide important findings in the future. LIMITATIONS Despite these findings, several areas remain elusive, including the possible differential role of toxic, inflammatory, hypoxic, and other components related to PBGs activity, as well as the possibility of modulating PBG function and BTSC homeostasis. With regard to NAS and OLT, it is also important to consider that several clinical variables aside from IRI may impact PVP integrity and PBG function, including rejection, immunosuppressive regimen, and the inflammatory background demonstrated by the association of NAS with OLT in PSC and AIH patients. Moreover, possible irreversible damage to the PVP during surgical manipulation should not be excluded. Finally, regenerative and proliferative processes of biliary epithelium are complex activities, finely tuned in the course of normal and pathological conditions by an intricate network of autocrine and paracrine signals coming from gastrointestinal hormones, angiogenic factors, neurotransmitters, and other molecules.[10] In this perspective, possible PBG isolation and culture would be (as also recognized by de Jong et al.[6]) a formidable system to assess the determinants leading to BSTC proliferation and differentiation in cholangiocytes or toward apoptosis, senescence, and also EMT. CONCLUSIONS AND FUTUREDIRECTIONS In conclusion, the study by de Jong et al. provides key data and information regarding loss of microvasculature during NAS after OLT. Furthermore, the investigators have demonstrated that PBG preservation is key to proper regeneration and bile duct integrity. The continuation of research regarding the interplay between PVP and PBGs will likely improve our comprehension of other human biliary diseases, in the future. CONFLICT OF INTEREST Nothing to report. AUTHOR CONTRIBUTIONS Francis ‐ prepared first draft, edited & approved final draft, funding. Kundu ‐ figure preparation & edited & approved final draft. Baiocchi ‐ prepared first draft & edited & approved final draft. FUNDING INFORMATION Supported by Indiana University Health, Indiana University School of Medicine Strategic Research Initiative, the VA Merit award to Dr. Francis (1I01BX003031) and Research Career Scientist Aw ard (IK6BX005226) from the United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service, and NIH grants DK108959 and DK119421 (Dr. Francis). This material results from work partially supported by resources at Richard L. Roudebush VA Medical Center (Indianapolis, IN)