Progenitor-Like Cells as an Etiological Factor and Potential Therapeutic Target in Alcohol-Induced Chronic Pancreatitis
Abstract
Veterans are a susceptible population to chronic pancreatitis (CP) due to heavy alcohol assumption. CP is a progressive disease that causes permanent pancreas damage, leading to food maldigestion. In addition to increased risk for fracture and deadly pancreatic adenocarcinoma, about 40% of CP patients develop diabetes. We still do not understand the reasons for CP development at the molecular level, which prevents us from designing effective treatments to cure this disease. Current paradigm suggests that the recurring stimulus such as chronic alcohol consumption induces the chronic smoldering inflammation to trigger CP progression. However, the fact that less than 10% of heavy drinkers develop CP implies that the way in which pancreatic cells respond to the insults may play a key role in determining pancreatitis progression. Unlike lung and gut, which use stem cells to repair tissue damage, the adult pancreas does not have stem cells. The digestion enzyme-producing acinar cells do not proliferate under the normal conditions. The pancreas injuries motivate them to assume the properties of progenitor-like cells in a process termed acinar-to-ductal metaplasia (ADM). The progenitor-like ADM cells decrease the enzyme production and start proliferating to replace the damaged cells. When progenitor-like cells ADM cells replenish the injured pancreas, they will undergo redifferentiation to become enzyme-producing acinar cells again. The previous studies mainly focused on the involvement of progenitor-like ADM cells in tissue repair during acute pancreatitis. However, these progenitor-like cells fail to re-differentiated to functional acinar cells and are accumulated in CP. The possibility that these progenitor-like cells might be responsible for CP progression has not been investigated. We hypothesize that the accumulated progenitor-like ADM cells will continuously send signals to get rid of “damaged cells,” which have already been removed by acute inflammation response. Thus, the other cells in the microenvironment are fooled by these wrong signals and trigger chronic smoldering inflammation to induce CP. Hippo pathway insufficiency is closely associated with existence of progenitor-like ADM cells in pancreas. We propose that insufficient Hippo pathway activity is a key defect leading to accumulation of progenitor-like ADM cells, thus sensitizing the individuals to CP development. Pharmaceutically targeting the key effectors in Hippo pathway might be a promising strategy to treatment CP. Our study will not only investigate the etiology of CP from a new perspective, the preclinical studies proposed will also generate important information to bridge the gaps between our basic science knowledge and the clinical demand for effective therapies to treat CP patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110079
Entities
People
- Jun Liu
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio