Bmi1 对于小鼠外分泌胰腺的再生是必需的。
Bmi1 is required for regeneration of the exocrine pancreas in mice.
机构信息
Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
出版信息
Gastroenterology. 2012 Sep;143(3):821-831.e2. doi: 10.1053/j.gastro.2012.05.009. Epub 2012 May 17.
BACKGROUND & AIMS: Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas.
METHODS
Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1(-/-) and wild-type primary acini were analyzed in vitro to determine acinar-specific consequences of Bmi1 deletion. To investigate cell autonomous versus non-cell autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1(-/-) mice reconstituted with a wild-type hematopoietic system.
RESULTS
Bmi1 expression was up-regulated in the exocrine pancreas during regeneration after cerulein-induced pancreatitis. Exocrine regeneration was impaired following administration of cerulein to Bmi1(-/-) mice. Pancreata of Bmi1(-/-) mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation compared with that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes was markedly up-regulated in Bmi1(-/-) pancreas compared with wild-type mice after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1(-/-) mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant but incomplete rescue of impaired exocrine regeneration after cerulein injury.
CONCLUSIONS
Bmi1 contributes to regeneration of the exocrine pancreas after cerulein-induced injury through cell autonomous mechanisms, in part by regulating Cdkn2a expression, and non-cell autonomous mechanisms.
背景与目的
Bmi1 是多梳蛋白家族的成员，通过修饰特定启动子处的染色质组织来抑制转录。Bmi1 参与干细胞自我更新的控制，并且已被证明可调节细胞增殖、组织动态平衡和分化。Bmi1 存在于自我更新的胰腺腺泡细胞的亚群中，并在胰腺损伤时表达。我们研究了 Bmi1 在胰腺外分泌部再生中的作用。
方法
用 cerulein 诱导 Bmi1(-/-) 小鼠发生急性胰腺炎；评估胰腺细胞再生、分化和凋亡。体外分析 Bmi1(-/-) 和野生型原代腺泡以确定 Bmi1 缺失的腺泡特异性后果。为了研究 Bmi1 在体内的细胞自主和非细胞自主作用，用野生型造血系统重建 Bmi1(-/-) 小鼠，诱导其发生胰腺炎。
结果
在 cerulein 诱导的胰腺炎后，Bmi1 在胰腺外分泌部的再生过程中表达上调。在 Bmi1(-/-) 小鼠中给予 cerulein 后，外分泌部的再生受损。Bmi1(-/-) 小鼠的胰腺体积较小，外分泌胰腺被导管化生取代，与野生型小鼠相比，其凋亡增加，细胞增殖减少。与野生型小鼠相比，Bmi1(-/-) 胰腺在损伤后，Cdkn2a 和 p53 依赖性凋亡基因的表达显著上调。此外，将来自野生型小鼠的骨髓移植到 Bmi1(-/-) 小鼠中后，嵌合体小鼠的胰腺发育不全程度处于中间水平，并且 cerulein 损伤后外分泌部再生受损得到部分但不完全的挽救。
结论
Bmi1 通过细胞自主机制，部分通过调节 Cdkn2a 表达，以及非细胞自主机制，促进 cerulein 诱导损伤后的外分泌胰腺再生。
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