β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas

Abstract

Novel strategies in diabetes therapy would obviously benefit from the use of beta (beta) cell stem/progenitor cells. However, whether or not adult beta cell progenitors exist is one of the most controversial issues in today's diabetes research. Guided by the expression of Neurogenin 3 (Ngn3), the earliest islet cell-specific transcription factor in embryonic development, we show that beta cell progenitors can be activated in injured adult mouse pancreas and are located in the ductal lining. Differentiation of the adult progenitors is Ngn3 dependent and gives rise to all islet cell types, including glucose responsive beta cells that subsequently proliferate, both in situ and when cultured in embryonic pancreas explants. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional beta cell mass by differentiation and proliferation rather than by self-duplication of pre-existing beta cells only.

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

“…Nestin, a non-endocrine lineage PPCM, was increased by IMT504 treatment in endothelial cells, pericytes and stellate cells, marking active regeneration [7] and angiogenesis [8]; this last variable was also indicated by increased CD31 in blood vessels. NGN3, an unambiguous marker for islet progenitors, was absent in normal islets and markedly increased in STZ-IMT504 rats, suggesting that IMT504 may be triggering NGN3 synthesis in pancreas-resident progenitor cells [9], similar to what was observed when administrating bone marrow-derived cells [10]. Our results are consistent with the view that the adult pancreas retains the potential to reactivate its embryonic mode of beta cell formation under the proper stimuli [11], and this capacity is greatly enhanced by IMT504.…”

“…Nevertheless, progenitor recruitment from other compartments may also occur. Lineage-tracing studies would provide important information in this regard [9,10].…”

Pancreas organogenesis: From bud to plexus to gland

“…A ligature around the main pancreatic duct results in distal damage, acinar involution, and an associated inflammatory response. Xu et al (2008) demonstrated that Ngn3 þ cells were induced in the duct epithelium after PDL, and thus identified a potential source of new endocrine cells in vivo. These Ngn3 þ duct cells, upon isolation, could produce all endocrine cell types when cultured in Ngn3 null pancreatic bud explants in vitro.…”

Attributes of adult stem cells

“…Direct lineage tracing, in which Cre recombinase was driven by a duct cell-specific promoter (carbonic anhydrase II), has shown that after pancreatic duct ligation (PDL), a population of less differentiated ductal cells emerges that expresses Pdx1 and contributes to islets [113]. PDL also causes up-regulation of the embryonic pancreas transcription factor Ngn3 in the ductal cells, and direct lineage tracing has also found that these cells can become insulin-positive cells [114].…”