The biliary epithelium is a complex network of interconnected ducts that increase in diameter from small to large bile ducts. It has been proposed that small cholangiocytes contain a population of biliary committed progenitors, showing expression of various biliary progenitor markers, and incorporate into neo-bile ducts at the sites of injury. When large cholangiocytes are damaged, small, Ca2+-dependent cholangiocytes are activated, acquiring phenotypic and functional features of large cholangiocytes and resulting in the repopulation of the injured large bile ducts. Cholestatic liver diseases (CLDs) such as Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC), are chronic diseases that slowly damage the intrahepatic and extrahepatic bile ducts including both small and large bile ducts. During CLDs and other human diseases, extracellular vesicles (EVs) are released by almost all cells (including hepatobiliary progenitors and cholangiocytes) in resting and activated conditions. Their mechanisms of actions are being elucidated and their potential role in health and disease is drawing increasing attention. However, the specific roles of non-coding RNAs (ncRNAs) in cholangiocytes derived EVs during hepatobiliary tissue repair (especially their characteristics during cholestatic liver injury) still need to be addressed. Based on our compelling data, we propose the central hypothesis that ncRNAs in small cholangiocytes derived extracellular vesicles contribute to the recovery of cholestatic liver injury through induction of growth and anti- senescence/anti-inflammation of hepatobiliary tissues and cells. In this application, we propose the systematic evaluation of stemness dependent ncRNAs as markers in small cholangiocytes derived EVs with the therapeutic potentials for cholestatic liver injury. We will address our central hypothesis by focusing on the following specific aims: 1) To define the biliary extracellular vesicle associated ncRNAs signaling involved in anti-inflammation process in hepatobiliary cells. In this study, we will characterize the interactions between miR-125b/let-7 and uc.338/uc.189 family members; define the role of anti-LPS ncRNA signaling in small cholangiocytes derived extracellular vesicles through flow cytometry and real-time PCR analysis. 2) To determine the effects of SMCC-EV associated ncRNAs on accelerating the morphologic and functional recovery of cholestatic liver injury in CLD mice induced in vivo by BDL or in the genetic mouse model of PSC and PBC, Mdr2-/- and dnTGFbRII, respectively. Therapeutic effects of EVs derived from SMCCs with miRNAs or inhibition of T-UCRs on hepatobiliary cell proliferation and inflammation, senescence and fibrosis will be evaluated. The results of the proposed studies may lead to new therapeutic strategies for human cholestatic liver diseases. Meanwhile, the acquired fundamental new knowledge about regulation of growth and tissue repair during cholestatic liver damage by hepatobiliary progenitors derived EVs is expected to advance the general field of anti-inflammatory biology and emerging therapeutic opportunities.

Public Health Relevance

It has been proposed that small cholangiocytes contain a population of biliary committed progenitors, showing expression of various biliary progenitor markers, and incorporate into neo-bile ducts at the sites of injury. The health relatedness of this grant proposal is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of the therapeutic functions of small cholangiocytes derived extracellular vesicles and increase opportunities for the development of novel treatment paradigms for the management of chronic liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054811-16
Application #
9831159
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2000-09-01
Project End
2021-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
16
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Wu, Nan; Meng, Fanyin; Zhou, Tianhao et al. (2018) The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-?1-Mediated Biliary Senescence. Am J Pathol 188:2264-2280
Zhou, Tianhao; Wu, Nan; Meng, Fanyin et al. (2018) Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 98:1449-1464
Ehrlich, Laurent; Scrushy, Marinda; Meng, Fanyin et al. (2018) Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 42:296-305
Sato, Keisaku; Meng, Fanyin; Venter, Julie et al. (2018) Author Correction: The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. Sci Rep 8:11238
Sato, Keisaku; Meng, Fanyin; Giang, Thao et al. (2018) Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 1864:1262-1269
Luo, Xianjun; Li, Honggui; Ma, Linqiang et al. (2018) Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology 155:1971-1984.e4
Cai, Yuli; Li, Honggui; Liu, Mengyang et al. (2018) Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity. Hepatology 68:48-61
Wu, Nan; Meng, Fanyin; Zhou, Tianhao et al. (2017) Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation. FASEB J 31:4305-4324
Wan, Ying; Meng, Fanyin; Wu, Nan et al. (2017) Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. Hepatology 66:528-541
Ehrlich, Laurent; Hall, Chad; Meng, Fanyin et al. (2017) A Review of the Scaffold Protein Menin and its Role in Hepatobiliary Pathology. Gene Expr 17:251-263

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