TNF-like weak inducer of apoptosis (TWEAK) promotes beta cell neogenesis from pancreatic ductal epithelium in adult mice

• Published in: PloS one Vol. 8; no. 8; p. e72132
• Main Authors: Wu, Fei, Guo, Lili, Jakubowski, Aniela, Su, Lihe, Li, Wan-Chun, Bonner-Weir, Susan, Burkly, Linda C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.08.2013; Public Library of Science (PLoS)
• Subjects: Acinar cells; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beta cells; Biology; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cost analysis; Cytokine TWEAK; Dentistry; Diabetes; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Growth factors; Histology; Humans; Hyperglycemia; Immunoglobulins; Immunohistochemistry; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Keratins - metabolism; Laboratory animals; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pancreas; Pancreas - metabolism; Pancreas - physiology; Pancreas - surgery; Pancreatectomy; Pancreatic Ducts - cytology; Pancreatic Ducts - drug effects; Pancreatic Ducts - metabolism; Paraffin; Progeny; Proteins; Receptors, Tumor Necrosis Factor - deficiency; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Regeneration; Regeneration - genetics; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Tamoxifen; Time Factors; Transgenic mice; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor Necrosis Factors - pharmacology; TWEAK Receptor; United States > US; Massachusetts; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072132

The 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. C57Bl/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-CreER(TM): 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. TWEAK 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. We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.