Abstract
Aim/HypothesisThe adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis) promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice.MethodsC57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreERTM: R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14) deficient mice after Px.ResultsTWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion.Conclusions/InterpretationWe conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.
Highlights
Diabetes mellitusis manifested as hyperglycemia resulting from inadequate production of insulin by pancreatic b-cells
FGF-inducible molecule 14 (Fn14) expression in the normal adult mouse pancreas was difficult to detect by immunostaining but was highly expressed by normal pancreatic duct cells at mRNA level (n = 3; values normalized to GAPDH were 0.014, 0.016, and 0.013, values comparable to positive control mouse lupus kidney samples); it is possible that Fn14 expression was upregulated during the isolation process
Fn14 deficiency delays pancreatic regeneration after Px Since our studies have shown that TNF-Like Weak Inducer of Apoptosis (TWEAK) overexpression induces pancreatic b-cell neogenesis in normal adult mice, we asked whether the endogenous TWEAK/Fn14 pathway plays a role in pancreatic regeneration
Summary
Diabetes mellitusis manifested as hyperglycemia resulting from inadequate production of insulin by pancreatic b-cells. Attempts to increase bcell mass through de novo pancreas regeneration or the expansion and differentiation of precursors in vitro for cell transplant therapy have been reported [1,2], with limited success due to lack of understanding of the identity of b-cell progenitors and mechanisms regulating their fate in adults. Numerous studies have determined that adult pancreas retains the intrinsic ability to make new insulin-producing b-cells, suggesting that facultative pancreatic progenitors exist within various cell types [3]. Ductal epithelium was definitively identified as the precursor for new endocrine cells and acinar cells both in neonates and after PDL in adults using the duct-specific carbonic anhydrase II (CAII) promoter to trace their fate [10]. Further investigation is warranted to elucidate pathways promoting pancreatic b-cell regeneration in adults
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