Cholangiocytes are the target cells in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by the damage, proliferation and differentiation of cholangiocytes of different sizes (i.e., small and large). Cholangiocyte differentiation and biliar remodeling are critical for the maintenance of biliary mass and the functional recovery during the pathogenesis of these devastating liver diseases. The elucidation of the intracellular mechanisms regulating the differential regenerative responses of small and large cholangiocytes to cholestasis and liver injury/toxins will play a pivotal role in the development o therapeutic strategies for the treatment of cholestatic liver diseases. During chronic hepatobiliary injury, a population of bipotent liver progenitor cells becomes activated to replenis both cholangiocytes and hepatocytes. If small cholangiocytes with multipotential capacity exist within human and rodent bile ducts, these cells should possess the ability to differentiate into either large cholangiocytes or hepatocytes during liver damage, such as diseased conditions in which large cholangiocytes or hepatocytes are lost or regenerative mechanisms are hampered. The plasticity of intrahepatic cholangiocytes has been postulated that terminally differentiated cells of one lineage may directly differentiate into another lineage or undergo trans-differentiation. Therefore, specific subpopulations of cells, such as small cholangiocytes that express known biliary progenitor cell markers, can be hypothesized to contain a multipotent cell population when exposed to certain pathological conditions. We propose the central hypothesis that small cholangiocytes contribute to the recovery of biliary injury through acquiring the phenotypes of liver progenitor cells and large cholangiocytes under diseased conditions. Systematic investigation of pluripotent genes and microRNAs is proposed in this application as markers in small cholangiocytes with the therapeutic potentials for cholestatic liver injury. The central hypothesis will be evaluated by three specific aims. First, we will distinguish pluripotent functional signaling pathways involved in tissue repair-related cellular functions in small and large cholangiocytes. Second, we will identify TGF-? dependent miRNAs involved in differentiation/regeneration-related cellular functions in small cholangiocytes. Last, we will determine the effects of small cholangiocytes and their-associated miRNAs on accelerating the morphologic and functional recovery of transgenic and chronic cholestatic liver injury in specific animal models. Therapeutic effects of cell engraft/miRNA manipulation on biliary cell growth and differentiation will be evaluated in vivo. Novel insights into the physiological roles and mechanisms of molecular and functional heterogeneity in human biliary epithelium will be obtained. Meanwhile, the fundamental knowledge obtained in the regulation of growth, differentiation and remodeling by small cholangiocytes/biliary committed progenitors is expected to advance the field of cholangiocyte biology/ pathophysiology.

Public Health Relevance

Bile duct cells have extensive reconstruction potential for impacting human health, and 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). Chronic cholestatic liver diseases cause damage/growth/reconstruction of bile ducts in the liver. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression/recovery 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 #
2R01DK054811-10A1
Application #
8779801
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doo, Edward
Project Start
2000-09-01
Project End
2017-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
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
Kennedy, Indsey; Francis, Heather; Meng, Fanyin et al. (2017) Diagnostic and therapeutic potentials of microRNAs in cholangiopathies. Liver Res 1:34-41
McMillin, Matthew; DeMorrow, Sharon; Glaser, Shannon et al. (2017) Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol 313:G410-G418
Hall, Chad; Ehrlich, Laurent; Venter, Julie et al. (2017) Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. Cancer Lett 386:179-188

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