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

Kelly Mcdaniel, Fanyin Meng, Nan Wu, Keisaku Sato, Julie Venter, Francesca Bernuzzi, Pietro Invernizzi, Tianhao Zhou, Konstantina Kyritsi, Ying Wan, Qiaobing Huang, Paolo Onori, Heather Francis, Eugenio Gaudio, Shannon Glaser, Gianfranco Alpini

Research output: Contribution to journalArticle

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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. Conclusion: 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.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - 2016
Externally publishedYes

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varespladib methyl
Bile Ducts
Liver
Wounds and Injuries
Ligation
Hepatic Stellate Cells
Sclerosing Cholangitis
Endoderm
Cholangitis
Stem Cells
Fibrosis
Laser Capture Microdissection
Severe Combined Immunodeficiency
Cell Aging
Methyltransferases
Therapeutic Uses
DNA Methylation
Cell- and Tissue-Based Therapy
Aspartate Aminotransferases
Alanine Transaminase

ASJC Scopus subject areas

  • Hepatology

Cite this

Mcdaniel, K., Meng, F., Wu, N., Sato, K., Venter, J., Bernuzzi, F., ... Alpini, G. (Accepted/In press). Forkhead box A2 regulated biliary heterogeneity and senescence during cholestatic liver injury in mice. Hepatology. https://doi.org/10.1002/hep.28831

Forkhead box A2 regulated 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, 2016.

Research output: Contribution to journalArticle

Mcdaniel, K, Meng, F, Wu, N, Sato, K, Venter, J, Bernuzzi, F, Invernizzi, P, Zhou, T, Kyritsi, K, Wan, Y, Huang, Q, Onori, P, Francis, H, Gaudio, E, Glaser, S & Alpini, G 2016, 'Forkhead box A2 regulated biliary heterogeneity and senescence during cholestatic liver injury in mice', Hepatology. https://doi.org/10.1002/hep.28831
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. / Forkhead box A2 regulated biliary heterogeneity and senescence during cholestatic liver injury in mice. In: Hepatology. 2016.
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AU - Mcdaniel, Kelly

AU - Meng, Fanyin

AU - Wu, Nan

AU - Sato, Keisaku

AU - Venter, Julie

AU - Bernuzzi, Francesca

AU - Invernizzi, Pietro

AU - Zhou, Tianhao

AU - Kyritsi, Konstantina

AU - Wan, Ying

AU - Huang, Qiaobing

AU - Onori, Paolo

AU - Francis, Heather

AU - Gaudio, Eugenio

AU - Glaser, Shannon

AU - Alpini, Gianfranco

PY - 2016

Y1 - 2016

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

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