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.

Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡ / Mcdaniel, Kelly; Meng, Fanyin; Wu, Nan; Sato, Keisaku; Venter, Julie; Bernuzzi, Francesca; Invernizzi, Pietro; Zhou, Tianhao; Kyritsi, Konstantina; Wan, Ying; Huang, Qiaobing; Onori, Paolo; Francis, Heather; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco. - In: HEPATOLOGY. - ISSN 0270-9139. - STAMPA. - 65:2(2017), pp. 544-559. [10.1002/hep.28831]

Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡

ONORI, PAOLO;GAUDIO, EUGENIO;
2017

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.
2017
hepatology; cholestatic liver injury; foxA2
01 Pubblicazione su rivista::01a Articolo in rivista
Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡ / Mcdaniel, Kelly; Meng, Fanyin; Wu, Nan; Sato, Keisaku; Venter, Julie; Bernuzzi, Francesca; Invernizzi, Pietro; Zhou, Tianhao; Kyritsi, Konstantina; Wan, Ying; Huang, Qiaobing; Onori, Paolo; Francis, Heather; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco. - In: HEPATOLOGY. - ISSN 0270-9139. - STAMPA. - 65:2(2017), pp. 544-559. [10.1002/hep.28831]
File allegati a questo prodotto
File Dimensione Formato  
McDaniel_Forkhead_2017.pdf

solo gestori archivio

Note: Hepatology. 2017 Feb;65(2):544-559. doi: 10.1002/hep.28831
Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 981.49 kB
Formato Adobe PDF
981.49 kB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/954212
Citazioni
  • ???jsp.display-item.citation.pmc??? 21
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 42
social impact