title: Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡.
abstract: Biliary-committed progenitor cells (small mouse cholangiocytes; SMCCs) from small bile ducts are more resistant to hepatobiliary injury than large mouse cholangiocytes (LGCCs) from large bile ducts. The definitive endoderm marker, forkhead box A2 (FoxA2), is the key transcriptional factor that regulates cell differentiation and tissue regeneration. Our aim was to characterize the translational role of FoxA2 during cholestatic liver injury. Messenger RNA expression in SMCCs and LGCCs was assessed by polymerase chain reaction (PCR) array analysis. Liver tissues and hepatic stellate cells (HSCs) from primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients were tested by real-time PCR for methylation, senescence, and fibrosis markers. Bile duct ligation (BDL) and multidrug resistance protein 2 (MDR2) knockout mice (MDR2-/-) were used as animal models of cholestatic liver injury with or without healthy transplanted large or small cholangiocytes. We demonstrated that FoxA2 was notably enhanced in murine liver progenitor cells and SMCCs and was silenced in human PSC and PBC liver tissues relative to respective controls that are correlated with the epigenetic methylation enzymes, DNA methyltransferase (DNMT) 1 and DNMT3B. Serum alanine aminotransferase and aspartate aminotransferase levels in nonobese diabetic/severe combined immunodeficiency mice engrafted with SMCCs post-BDL showed significant changes compared to vehicle-treated mice, along with improved liver fibrosis. Enhanced expression of FoxA2 was observed in BDL mouse liver after SMCC cell therapy. Furthermore, activation of fibrosis signaling pathways were observed in BDL/MDR2-/-mouse liver as well as in isolated HSCs by laser capture microdissection, and these signals were recovered along with reduced hepatic senescence and enhanced hepatic stellate cellular senescence after SMCC engraft.
  
  
  
  The definitive endoderm marker and the positive regulator of biliary development, FoxA2, mediates the therapeutic effect of biliary-committed progenitor cells during cholestatic liver injury. (Hepatology 2017;65:544-559).
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX.|Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.|Research Institute, Baylor Scott & White Health, Temple, TX.
authors.forename: Kelly
authors.initials: K
authors.lastname: McDaniel
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX.|Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.|Research Institute, Baylor Scott & White Health, Temple, TX.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Keisaku
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Kyritsi
authors.affiliation: Research Institute, Baylor Scott & White Health, Temple, TX.|Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, China.
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX.|Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.|Research Institute, Baylor Scott & White Health, Temple, TX.
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX.|Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX.|Department of Medicine, Baylor Scott & White Health Digestive Disease Research Center, Texas A&M HSC and Baylor Scott & White Health, Temple, TX.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002450:Cell Communication / Q000235:genetics; D002779:Cholestasis / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000293:injuries* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies
chemical_list: C496503:Foxa2 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta