Department of Immunobiology, Biogen Idec, Cambridge, Massachusetts, United States of America.
PLoS One. 2013 Aug 26;8(8):e72132. doi: 10.1371/journal.pone.0072132. eCollection 2013.
AIM/HYPOTHESIS: 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.
CONCLUSIONS/INTERPRETATION: We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.
目的/假设：成年哺乳动物的胰腺再生能力有限，无法从多能祖细胞中产生足够的胰岛素，而这些祖细胞的特性和功能仍知之甚少。在这里，我们检测 TNF 家族成员 TWEAK（TNF 样凋亡弱诱导物）是否能促进成年小鼠增殖的胰腺导管上皮细胞向 β 细胞新生。
C57Bl/6J 小鼠用 Fc-TWEAK 处理，并在不同时间点采集胰腺组织进行组织学和免疫组织化学分析。为了进行谱系追踪，4 周龄的双转基因小鼠 CAII-CreER(TM): R26R-eYFP 植入他莫昔芬丸，每周两次注射 Fc-TWEAK 或对照 Ig，并在第 18 天通过胰岛素和 YFP 共染色分析 TWEAK 诱导的导管细胞祖细胞。通过对野生型和 TWEAK 受体（Fn14）缺失小鼠 Px 后石蜡包埋切片的全细胞角蛋白免疫染色，确定 TWEAK 对胰腺再生的影响。
TWEAK 通过其受体 Fn14 刺激导管上皮细胞增殖，而对胰腺 α 或 β 细胞或腺泡细胞没有有丝分裂作用。重要的是，TWEAK 诱导内源性 Ngn3 的瞬时表达，Ngn3 是内分泌细胞发育的主要调节因子，并诱导具有再生焦点特征的局灶性导管结构。此外，我们通过谱系追踪鉴定出 TWEAK 诱导的胰腺 β 细胞来源于胰腺导管上皮细胞。相反，我们发现 Fn14 缺乏会延迟 Px 后再生焦点的形成，并限制其扩张。
结论/解释：我们的结论是，TWEAK 是一种在正常成年小鼠中介导胰腺导管上皮向 β 细胞新生的新型因子。
