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  • The identification of stem cells or progenitor cells

    2018-11-12

    The identification of stem SB 431542 or progenitor cells, and their contribution to pancreatic regeneration remain controversial (Ziv et al., 2013; Burke and Tosh, 2012). The pancreas uses several regenerative mechanisms. Self-renewal is the principal mechanism of acinar and islet regeneration in response to inflammatory injury (Strobel et al., 2007a, 2007b; Dor et al., 2004), however, little is known about pancreatic ductal epithelial renewal. Multipotential stem cells have been reported to reside in the pancreatic duct (Bonner-Weir and Sharma, 2002), islets, centroacinar or acinar cells and have the capacity for duct-like cell fates. (Pan et al., 2013; Rovira et al., 2010; Kopp et al., 2011; Reichert and Rustgi, 2011; Puri et al., 2015). Recently our group identified a novel epithelial compartment, termed pancreatic duct glands (PDGs), which may function as a ductal epithelial progenitor niche (Strobel et al., 2010). PDGs are gland-like outpouches or coiled glands residing within the mesenchymal cuff of surrounding large ducts. PDGs have a unique molecular profile distinct from glands of the normal pancreatic epithelium. They also express developmental markers known to reside in GI progenitor stem cell niches, such as Shh, Pdx-1 and Hes-1. In response to inflammatory injury, epithelial proliferation is up-regulated predominantly in the PDG compartment, suggesting that this may be an epithelial progenitor compartment for the pancreatic ductal epithelium.
    Methods
    Results
    Discussion The existence of somatic stem cells in the pancreas and their contribution toward pancreatic epithelial renewal and regeneration after injury are poorly understood. Here we report that PDGs, a novel epithelial compartment (Strobel et al., 2010), function as a pancreatic ductal epithelial progenitor niche. This work reveals that the PDGs are the principal site of epithelial proliferation and new cell formation. In vivo tag-and-chase experiments reveal that these newly generated cells migrate from the PDGs to populate the pancreatic ductal epithelium. Furthermore, this compartment is capable of giving rise to differentiated progeny distinct from the parent cell. The genes expressed in this unique compartment are found to be enriched for core regulators of embryonic stem cell pluripotency and genes important in intestinal and colonic stem cells regulation. Taken together, this data suggests that the PDGs are a progenitor stem cell compartment responsible for pancreatic ductal epithelial regeneration. The pancreas may employ several regenerative mechanisms, depending on the compartment. Like the liver, the pancreatic acinar and beta cell compartments regenerate by self-duplication. Although a population of ALDH1 centroacinar/terminal ductal cells has been identified and found to have multipotential function (Rovira et al., 2010), in vivo lineage tagging studies by our group and others demonstrate that the principal mode of regeneration of the islets and acinar compartment in response to inflammatory injury is dependent not on stem cells but rather on self-duplication (Strobel et al., 2007a, 2007b; Dor et al., 2004). The pancreatic ductal epithelium, however, appears to be more like the gastrointestinal epithelium, relying on a stem cell niche for regeneration. Although BrdU incorporation and the tag-and-chase experiment suggest that the pancreatic ductal epithelium is regenerated from the PDG compartment, this methodology does have limitations and lineage tagging studies will ultimately be needed to make definitive conclusions. In this inflammatory model the pancreatic epithelium has several proliferating (BrdU incorporating) compartments: the PDGs (found in the proximal and central pancreatic ductal epithelium), the terminal ducts, islets and the acinar cells. In vivo lineage tracing of the acinar and beta cell compartments reveals that tagged events were never identified in the pancreatic ductal epithelium, suggesting that neither the acinar cells nor the beta cells are capable of regenerating the ductal epithelium (Strobel et al., 2007a, 2007b). The PDGs appear to be important in regenerating the proximal to distal pancreatic ductal epithelium. However, the pancreatic epithelium is heterogeneous, and the contribution of the PDGs to regeneration of the terminal ducts remains unknown. Although PDGs have been found throughout the pancreas, PDG-like cells have not been identified in the terminal duct system (Strobel et al., 2010). In response to inflammatory injury, terminal ducts themselves possess a high proliferative rate (Strobel et al., 2007a); thus the mechanism of regeneration of the terminal ducts likely does not rely on the PDG compartment.