Pancreatic Inactivation of c-Myc Decreases Acinar Mass and Transdifferentiates Acinar Cells Into Adipocytes in Mice
Pancreatic Inactivation of c-Myc Decreases Acinar Mass and Transdifferentiates Acinar Cells Into Adipocytes in Mice
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DOI：
10.1053/j.gastro.2008.10.015
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发表时间：
2009-01-01
期刊：
影响因子：
29.4
通讯作者：
Herrera, Pedro L.
中科院分区：
文献类型：
--
作者：
Bonal, Claire;Thorel, Fabrizio;Herrera, Pedro L.
背景和目标：胰腺质量由祖细胞的协调扩增和分化决定，并通过严格控制细胞置换率来维持。碱性螺旋-环-螺旋转录因子c-Myc是许多器官中这些过程的主要调节因子之一。我们研究了c-Myc在控制胰腺肿块的产生和维持中的需求。方法：我们在Pdx 1+胰腺祖细胞中条件性灭活c-Myc。在发育和衰老期间分析缺乏c-Myc的小鼠（c-Myc（P-/-）小鼠）的胰腺。结果如下：胰腺生长在c-Myc（P-/-）小鼠E12.5开始受损，在早期原基，因为减少增殖和改变分化的外分泌祖细胞;胰岛祖细胞幸免。腺泡细胞的成熟是有缺陷的，在成人营养不良的胰腺，这阻碍了外分泌质量维持老年动物。从2至10月龄，c-Myc（P-/-）胰腺进行性重塑，无炎性损伤。随着时间的推移，腺泡细胞的损失增加，伴随着脂肪组织的积累。利用遗传细胞谱系追踪分析，我们证明胰腺脂肪细胞直接来源于转分化的腺泡细胞。在正常老年标本和胰腺炎中也观察到上皮细胞向间充质细胞的转变。结论：这些结果提供的证据表明，c-Myc活性是必需的外分泌胰腺的生长和成熟，并揭示了新的光胰腺脂肪细胞在器官退化和组织退化的过程中的个体发育。
Background & Aims: The pancreatic mass is determined by the coordinated expansion and differentiation of progenitor cells and is maintained via tight control of cell replacement rates. The basic helix-loop-helix transcription factor c-Myc is one of the main regulators of these processes in many organs. We studied the requirement of c-Myc in controlling the generation and maintenance of pancreatic mass. Methods: We conditionally inactivated c-Myc in Pdx1+ pancreatic progenitor cells. Pancreata of mice lacking c-Myc (c-Myc(P-/-) mice) were analyzed during development and ageing. Results: Pancreatic growth in c-Myc(P-/-) mice was impaired starting on E12.5, in early primordia, because of decreased proliferation and altered differentiation of exocrine progenitors; islet progenitors were spared. Acinar cell maturation was defective in the adult hypotrophic pancreas, which hampered exocrine mass maintenance in aged animals. From 2 to 10 months of age, the c-Myc(P-/-) pancreas was progressively remodeled without inflammatory injury. Loss of acinar cells increased with time, concomitantly with adipose tissue accumulation. Using a genetic cell lineage tracing analysis, we demonstrated that pancreatic adipose cells were derived directly from transdifferentiating acinar cells. This epithelial-to-mesenchyme transition was also observed in normal aged specimens and in pancreatitis. Conclusions: These results provide evidence indicating that c-Myc activity is required for growth and maturation of the exocrine pancreas, and sheds new light on the ontogeny of pancreatic adipose cells in processes of organ degenerescence and tissue involution.