Human liver is innervated by a dense network of extrinsic and intrinsic nerves that regulate liver regeneration. Cholangiocyte differentiation and biliary remodeling are critical for the maintenance of biliary mass, and the functional recovery during the pathogenesis of cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). With regard to the plasticity of intrahepatic cholangiocytes, it has been postulated that terminally differentiated cells of one lineage may directly differentiae 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 that may be activated when exposed to certain pathological conditions. We have previously demonstrated a direct role for the parasympathetic and sympathetic innervation in the regulation of biliary mass and cholangiocyte functional activity. Although sensory innervation is present in the liver as dense neural networks in the fibromuscular layer of the biliary epithelium, little information exists regarding its role n the regulation of biliary proliferation and function in normal and diseased states. Our preliminary studies have indicated that small cholangiocytes possess functional pluripotent characteristics under conditions that large more senescent cholangiocytes are damaged or lost. During the damage of large cholangoicytes, this pluripotent cell population is activated by the sensory neuropeptides to repopulate damaged bile ducts and livers. Based on these compelling data, we propose the central hypothesis that small murine cholangiocytes contribute to the recovery of biliary injury through acquiring the sensory neuropeptides regulated phenotypes of large cholangiocytes under diseased conditions. The central hypothesis will be evaluated by the following three specific aims: (1) substance P (SP)-dependent sensory innervation involved in the regulation of tissue repair-related cellular functions in small and large cholangoicytes will b identified, (2) the functional role of SP- dependent miRNAs involved in differentiation-related cellular functions in biliary committed progenitors will be defined, (3) the effects of SP-associated mRNAs and miRNAs on accelerating the morphologic and functional recovery of biliary damage during chronic cholestatic liver injury in vivo. Therefore, a systematic evaluation of substance P-regulated pluripotent genes and microRNAs as markers in small cholangiocytes with the therapeutic potentials for cholestatic liver injury is proposed in this application. In addition, the translational role of the selective manipulation of gene/miRNA on biliary cell differentiation will be evaluated. The completion of the proposed studies may lead to alternative therapeutic strategies for human biliary injury. Novel insights into the mechanisms of sensory neuropeptides regulate heterogeneity in human biliary tree will be obtained. This newly acquired fundamental knowledge about regulation of differentiation by sensory neuropeptide-regulated mRNAs and miRNAs in biliary progenitors will advance the general field of cholangiocyte biology.

Public Health Relevance

Cholangiocytes have extensive potential for the reconstruction of the liver that is regulated by neuroendocrine factor substance P 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 and increase opportunities for the development of novel treatment paradigms for the maintenance of liver homeostasis during 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 #
2R01DK076898-04
Application #
8588378
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (03))
Program Officer
Sherker, Averell H
Project Start
2006-12-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$291,782
Indirect Cost
$48,201
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
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
Sato, Keisaku; Hall, Chad; Glaser, Shannon et al. (2016) Pathogenesis of Kupffer Cells in Cholestatic Liver Injury. Am J Pathol 186:2238-47
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 :

Showing the most recent 10 out of 63 publications