Peribiliary glands (PBGs) are located in the large intrahepatic and extrahepatic bile ducts. Although they were described many years ago, their functions have been elucidated only in the last couple of years when our group demonstrated that PBGs are niches of multipotent stem/progenitor cells of endodermal origin. These cells express genes of multipotency and can be rapidly differentiated in vitro into hepatocytes, cholangiocytes, and endocrine pancreatic cells. PBGs share common features, in terms of stem/progenitor cell niches, with pancreatic duct glands and colon crypts, glandular structures representing in the adult life the endodermal remnants of fetal life. PBG stem/progenitor cells participate in the renewal of surface biliary epithelium and are active players in chronic pathologies of the biliary tree as well as in cholangiocarcinomas (CCA). Specifically, a large amount of recent evidence indicates that the pure mucin-CCA originates from PBGs; this could explain the similarities with pancreatic ductal adenocarcinoma and colorectal cancer, which also originate from transformed gland cells. In this paper, we summarized our recent findings concerning structure and functions of PBGs with the implications for liver pathophysiology and, specifically, for cancers of the biliary tree. 1. Introduction Although peribiliary glands (PBGs) have been described for many years, their functions were clarified only a couple of years ago when our group demonstrated that niches of multipotent stem/progenitor cells of endodermal origin are located at the bottoms of these glands. This observation and subsequent research from our group are highlighting a relevant role of PBGs in liver pathophysiology with important implications for the renewal of biliary epithelium and liver parenchyma as well as for the pathogenesis of chronic liver diseases and liver cancers. In this paper we summarize our recent findings in the area of PBGs with a specific focus on the implications for the origin and pathogenesis of cholangiocarcinoma (CCA). 2. Anatomy and Physiology of Peribiliary Glands The biliary tree is composed of intrahepatic (IH) and extrahepatic (EH) bile ducts lined by epithelial cells called cholangiocytes. For many years, in humans and in other animal species [1] (mouse, rat, pig, monkey, dog, pig, cow, sheep, and rabbit) glandular elements along the biliary tree have been described and named peribiliary glands (PBGs) [2] (Figure 1). PBGs are tubular-alveolar structures composed of serous and mucinous acini located in the EH and large IH bile ducts [3] (Figure 1). We
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