Abstract
Tubular complexes (TCs) are aggregates of duct-like monolayered cells in the developing and regenerating pancreas. Recent studies showed that TCs have regenerative potential, including islet neogenesis. We previously delivered adenovirus vector (AdV) into exocrine cells of the pancreas by intra-common bile ductal (ICBD) injection, and found that AdV expressing Pdx1, a pancreas-specific transcription factor, causes TC formation and islet neogenesis. We also established RTF-Pdx1-EGFP mice, which ubiquitously express Pdx1 when tetracycline is removed from the drinking water. However, exogenous Pdx1 expression in adult RTF-Pdx1-EGFP mice did not cause any pathological changes in the pancreas during three weeks of observation after tetracycline withdrawal. To examine whether the host immune response induced by AdV was involved in TC formation, we delivered AdVs expressing pancreas-related transcription factors or an irrelevant protein into the pancreas of RTF-Pdx1-EGFP mice. Histological analyses showed that both AdV injection and Pdx1 expression are required for TC formation. We also analyzed the effects of these ICBD-injected AdVs. AdV expressing Isl1, a proendocrine transcription factor, effectively induced TC formation through acinar-to-ductal metaplasia, and exogenous Pdx1 expression facilitated this process. Considering the regenerative potential of TCs, a strategy that efficiently induces TC formation may lead to novel therapies for diabetes.
Highlights
Current therapies for type 1 diabetes, such as daily insulin injections, cannot prevent the progression of secondary complications
We examined the effects of intra-common bile ductal (ICBD) injection of adenovirus vector (AdV) expressing pancreas-related transcription factors and a control AdV expressing an irrelevant protein into RTFPdx1-EGFP mice
The transgenic expression of Pdx1 in the pancreas of adult mice did not cause any pathological changes in this organ during three weeks of observation, which appeared inconsistent with our previous observation that the transfer of AdV-Pdx1 into the pancreas led to tubular complexes (TCs) formation and islet neogenesis
Summary
Current therapies for type 1 diabetes, such as daily insulin injections, cannot prevent the progression of secondary complications. After 90% pancreatectomy, adult rats show substantial pancreatic regeneration that is achieved by the replication of both preexisting endocrine and exocrine cells and the proliferation of ducts, which subsequently differentiate into new pancreatic lobes [3], and increased islet neogenesis has been reported in a number of other experimental systems [4,5]. Other studies suggest that adult pancreatic acinar tissue can transform into various pancreatic cell types through acinar-to-ductal transdifferentiation [13,14,15] Regardless of this controversy, the ability to induce TC formation followed by duct-to-endocrine redifferentiation could lead to new therapies for diabetic hyperglycemia. It is important to clarify the molecular mechanisms underlying TC formation and subsequent islet neogenesis
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