Activated Macrophages Create Lineage-Specific Microenvironments for Pancreatic Acinar- and β-Cell Regeneration in Mice

Pancreatic Regeneration: Models, Mechanisms, and Inconsistencies

“…Thus, transgenic expression of the simian or human DTR in mice can render naturally DT-resistant mouse cells DTsensitive (14,37,67 (17,18). In the adult pancreas, DTR/DTA-mediated β-cell ablation has been used to study regeneration following α-or β-cell specific losses (15,17,57,70,78), acinar (17,18), or acinar and endocrine cell ablation (17,18).…”

“…Necrosis, on the other hand is invoked in response to external stimuli and ATP-deficiency (22). Pancreatic injury and ensuing regeneration invariably depend on proper clearance of the dead cells (17). Because of its nature (loss of cytoplasmic membrane integrity, cellular fragmentation and release of lysosomal and granular contents into surrounding extracellular space), necrosis does not allow for proper removal of cell organelles, and as the result it is followed by reactive inflammation (2,12,22,50,58,68).…”

“…The effect of apoptosis or necrosis on regeneration is perhaps best manifested when one compares β-cell regeneration following STZ (or alloxan) treatment with DT-mediated β-cell ablation. In these two models, the target cells (β-cells) as well as the degree of β-cell loss (75-80% sub-optimal condition for STZ, or 75% β-cell ablation using PdxCreERT) are similar (17,21). Interestingly, STZ-induced necrosis is accompanied with a massive inflammatory response and the absence of β-cell regeneration, whereas DT-induced apoptosis leads to almost complete β-cell mass recovery (57).…”

“…Acinar regeneration appears to be less sensitive to the nature of injury, as robust acinar tissue recovery have been reported in both necrotic (caerulein) as well as apoptotic (DTmediated) environments (17,18,28,33,36,53,54,72).…”

“…The adult pancreas displays a limited capacity to regenerate, although this regenerative capacity declines with age (17,(74)(75)(76)83). Thus, with respect to the pancreas, the uncertainty is not about the overall ability of the adult pancreas to regenerate, but rather which cells may act as cell(s) of origin in this process.…”