Abstract
BackgroundPancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce beta cell generation and increase beta cell mass but increases in beta cell number have not been demonstrated. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates.MethodologyTotal beta cell number and its distribution over small (<50 µm), medium, large (>100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham.Principal findingsPDL increased total beta cell mass but not total beta cell number. It induced neogenesis of small beta cell clusters (2.2-fold higher number) which contained a higher percent proliferating beta cells (1.9% Ki67+cells) than sham tails (<0.2%); their higher beta cell number represented <5% of total beta cell number and was associated with a similar increase in alpha cell number. It is unknown whether the regenerative process is causally related to the inflammatory infiltration in PDL-tails. Human pancreases with inflammatory infiltration also exhibited activation of proliferation in small beta cell clusters.Conclusions/significanceThe PDL model illustrates the advantage of direct beta cell counts over beta cell mass measurements when assessing and localizing beta cell regeneration in the pancreas. It demonstrates the ability of the adult mouse pancreas for neogenesis of small beta cell clusters with activated beta cell proliferation. Further studies should investigate conditions under which neoformed small beta cell clusters grow to larger aggregates and hence to higher total beta cell numbers.
Highlights
[1] They were identified as ngn3-expressing cells that were induced by duct ligation, and that preceded an increase in beta cell mass
Leucocytes do occur in unligated tissue, but they are so scarce that a ‘‘concentration’’ effect following acinar cell depletion can only partially explain their numbers in Pancreatic-tail duct ligation (PDL)-tails; their higher abundance at week 1 is consistent with an infiltration
Two weeks after duct ligation, tails exhibited a 60 percent higher beta cell mass, which is consistent with the rise reported by previous studies [1,2,8,9]
Summary
Beta cell progenitor cells have recently been reported in the adult mouse pancreas [1] They were identified as ngn3-expressing cells that were induced by duct ligation, and that preceded an increase in beta cell mass These cells were shown to differentiate to beta cells, it was not clear to which extent this process was responsible for an increase in beta cell number. We have used this method to investigate whether PDL in adult mice increases their total beta cell number, and, if so, whether this involves neoformation of small beta cell clusters and/or their growth to larger aggregates. PDL was not found to increase total beta cell numbers but induced the neoformation of small beta cell clusters with elevated levels of proliferating beta cells This finding led us to investigate the small clusters in human donor organs that contained inflammatory cell infiltrates, similar to those observed in the ligated mouse pancreas. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates
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