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

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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

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

doi

10.1053/j.gastro.2014.02.030

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

1795-808.e12

issue

7

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(14)00241-8

journal_volume

146

pub_type

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