Tracing cell lineages in health and disease: experimental and human studies
This study aimed to investigate stem cell biology in the normal and diseased pancreas and liver employing robust methods for tracking stem cells and their progeny in both pre-clinical and human scenario. Bone marrow (BM) plasticity had been demonstrated in diseased organ remodelling. By detection of the Y chromosome in female mice receiving a sexmismatch BM transplantation, BM-derived cells were present in murine pancreas with cerulein-induced pancreatitis. BM-derived myofibroblasts functionally contributed to around 8% of the total population of myofibroblasts, the cells with a key fibrogenic role. Fibrocytes are circulating pro-fibrogenic cells; a decrease of BM-derived fibrocytes in blood and detection of these cells in areas of collagen deposition indicated they migrated to inflamed pancreas and played a role in extracellular matrix formation. IL-10 is an anti-inflammatory cytokine mainly secreted by BM; a lack of IL-10 increased the fibrosis, the inflammation and the numbers of BM-derived myofibroblasts suggesting a potential role of IL-10 in chronic pancreatitis. Mitochondrial DNA (mtDNA) mutations permit lineage tracing within human tissues. Cells having identical mtDNA mutations within a cytochrome c oxidase (CCO)- deficient area must be related having originated from a common founder cell, presumably a stem cell. I have demonstrated that regenerative nodules in cirrhotic liver are invariably clonal populations, and that these nodules often originate from progenitor cells from the abutting ductular reactions. An attempt to build a phylogenetic tree based on the accumulation of mutations in normal liver reinforced the belief that hepatic stem cells are located within the portal tract area and that their cell progeny migrate centrifugally from the portal tract region. The same techniques were applied to the pancreas, but many areas of CCO deficiency could be ascribed to autolysis, while the 3 discovery of identical mtDNA base changes within and outwith CCO-deficient patches suggested these were genetic polymorphisms, previously unreported.
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