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
Kennedy, Lindsey L; Meng, Fanyin; Venter, Julie K et al. (2016) Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice. Lab Invest 96:1256-1267
McDaniel, Kelly; Hall, Chad; Sato, Keisaku et al. (2016) Lin28 and let-7: roles and regulation in liver diseases. Am J Physiol Gastrointest Liver Physiol 310:G757-65
Wu, Nan; Meng, Fanyin; Invernizzi, Pietro et al. (2016) The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-β1 biliary secretion in mice. Hepatology 64:865-79
Johnson, Christopher; Huynh, Victoria; Hargrove, Laura et al. (2016) Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor-Dependent Signaling. Am J Pathol 186:123-33
Han, Yuyan; Meng, Fanyin; Venter, Julie et al. (2016) miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J Hepatol 64:1295-304
Wan, Ying; Garner, Jessica; Wu, Nan et al. (2016) Role of stem cells during diabetic liver injury. J Cell Mol Med 20:195-203
Hall, Chad; Sato, Keisaku; Wu, Nan et al. (2016) Regulators of Cholangiocyte Proliferation. Gene Expr :
Sato, Keisaku; Meng, Fanyin; Glaser, Shannon et al. (2016) Exosomes in liver pathology. J Hepatol 65:213-21
McDaniel, Kelly; Meng, Fanyin; Wu, Nan et al. (2016) Forkhead box A2 regulated biliary heterogeneity and senescence during cholestatic liver injury. Hepatology :
Venter, Julie; Francis, Heather; Meng, Fanyin et al. (2015) Development and functional characterization of extrahepatic cholangiocyte lines from normal rats. Dig Liver Dis 47:964-72

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