Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice

Shannon Glaser, Fanyin Meng, Yuyan Han, Paolo Onori, Billy K. Chow, Heather Francis, Julie Venter, Kelly McDaniel, Marco Marzioni, Pietro Invernizzi, Yoshiyuki Ueno, Jia Ming Lai, Li Huang, Holly Standeford, Domenico Alvaro, Eugenio Gaudio, Antonio Franchitto, Gianfranco Alpini

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background & Aims Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. Methods Cholestasis was induced in secretin knockout (Sct-/-) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct-/- mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. Results Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct-/- mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. Conclusions After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.

Original languageEnglish (US)
JournalGastroenterology
Volume146
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Secretin
MicroRNAs
Cell Proliferation
Bile Ducts
Ligation
Morpholinos
Nerve Growth Factor
Intrahepatic Bile Ducts
Vascular Endothelial Growth Factor A
Liver
Knockout Mice
Bile
Cholestasis
Conditioned Culture Medium
Luciferases
Serum
Tail
Real-Time Polymerase Chain Reaction
Veins
Up-Regulation

Keywords

  • Biliary Epithelium
  • cAMP
  • Gastrointestinal Hormones
  • Heterogeneity

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice. / Glaser, Shannon; Meng, Fanyin; Han, Yuyan; Onori, Paolo; Chow, Billy K.; Francis, Heather; Venter, Julie; McDaniel, Kelly; Marzioni, Marco; Invernizzi, Pietro; Ueno, Yoshiyuki; Lai, Jia Ming; Huang, Li; Standeford, Holly; Alvaro, Domenico; Gaudio, Eugenio; Franchitto, Antonio; Alpini, Gianfranco.

In: Gastroenterology, Vol. 146, No. 7, 2014.

Research output: Contribution to journalArticle

Glaser, S, Meng, F, Han, Y, Onori, P, Chow, BK, Francis, H, Venter, J, McDaniel, K, Marzioni, M, Invernizzi, P, Ueno, Y, Lai, JM, Huang, L, Standeford, H, Alvaro, D, Gaudio, E, Franchitto, A & Alpini, G 2014, 'Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice', Gastroenterology, vol. 146, no. 7. https://doi.org/10.1053/j.gastro.2014.02.030
Glaser, Shannon ; Meng, Fanyin ; Han, Yuyan ; Onori, Paolo ; Chow, Billy K. ; Francis, Heather ; Venter, Julie ; McDaniel, Kelly ; Marzioni, Marco ; Invernizzi, Pietro ; Ueno, Yoshiyuki ; Lai, Jia Ming ; Huang, Li ; Standeford, Holly ; Alvaro, Domenico ; Gaudio, Eugenio ; Franchitto, Antonio ; Alpini, Gianfranco. / Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice. In: Gastroenterology. 2014 ; Vol. 146, No. 7.
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abstract = "Background & Aims Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. Methods Cholestasis was induced in secretin knockout (Sct-/-) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct-/- mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. Results Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct-/- mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. Conclusions After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.",
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T1 - Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice

AU - Glaser, Shannon

AU - Meng, Fanyin

AU - Han, Yuyan

AU - Onori, Paolo

AU - Chow, Billy K.

AU - Francis, Heather

AU - Venter, Julie

AU - McDaniel, Kelly

AU - Marzioni, Marco

AU - Invernizzi, Pietro

AU - Ueno, Yoshiyuki

AU - Lai, Jia Ming

AU - Huang, Li

AU - Standeford, Holly

AU - Alvaro, Domenico

AU - Gaudio, Eugenio

AU - Franchitto, Antonio

AU - Alpini, Gianfranco

PY - 2014

Y1 - 2014

N2 - Background & Aims Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. Methods Cholestasis was induced in secretin knockout (Sct-/-) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct-/- mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. Results Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct-/- mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. Conclusions After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.

AB - Background & Aims Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. Methods Cholestasis was induced in secretin knockout (Sct-/-) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct-/- mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. Results Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct-/- mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. Conclusions After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.

KW - Biliary Epithelium

KW - cAMP

KW - Gastrointestinal Hormones

KW - Heterogeneity

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