Expansion and Maintenance of CD133-Expressing Pancreatic Ductal Epithelial Cells by Inhibition of Transforming Growth Factor-beta Signaling
Expansion and Maintenance of CD133-Expressing Pancreatic Ductal Epithelial Cells by Inhibition of Transforming Growth Factor-beta Signaling
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通过抑制转化生长因子-β信号传导来扩增和维持表达 CD133 的胰腺导管上皮细胞
DOI：
10.1089/scd.2019.0087
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发表时间：
2019
影响因子：
4
通讯作者：
Jin Liang
中科院分区：
文献类型：
--
作者：
Zhang Fangfang;Ma Dongshen;Liu Tingsheng;Liu Yu Hong;Guo Jiamin;Song Jing;Wu Qiong;Pan Yi;Zhang Yanfeng;Guo Changying;Teng Chunbo;Jin Liang
胰岛移植恢复β细胞质量是一种有效的糖尿病治疗方法，但受供体器官短缺的限制。表达cd133的胰腺导管上皮细胞（PDECs）具有产生胰岛素生成细胞的能力。这些细胞的扩张依赖于外部生态位因子，但这些信号很少被确定。本研究通过从成年野生型C57BL/6小鼠和tgf - β riinull / null小鼠中分选纯化表达cd133的PDECs。此外，通过免疫荧光和移植实验，我们发现对转化生长因子-β (TGF-β)通路的抑制促进了表达cd133的PDECs的扩增，并维持了表达cd133的PDECs产生胰岛素细胞的能力。此外，使用TGF-β抑制剂进行western blot、qRT-PCR和双荧光素酶检测，以确定TGF-β信号通路调节增殖和分化的机制。结果表明，抑制TGF-β信号通路可增强edid2与细胞增殖抑制因子p16启动子区的结合，促进表达cd133的PDECs扩增，edid2结合toneurod1的增加可降低pax6的转录，维持pdx1表达阶段表达cd133的PDECs。综上所述，TGF-β拮抗剂对表达cd133的PDECs的影响揭示了一种新的信号传导模式，解释了胰管上皮祖细胞扩张和分化之间的平衡。
Restoring β-cell mass by the transplantation of pancreatic islets is an effective diabetes treatment, but it is limited by the shortage of donor organs. CD133-expressing pancreatic ductal epithelial cells (PDECs) have the ability to generate insulin-producing cells. The expansion of these cells is dependent on extrinsic niche factors, but few of those signals have been identified. In this study, CD133-expressing PDECs were purified by sorting from adult wild-type C57BL/6 mice and TGFβRIInull/nullmice. Furthermore, using immunofluorescence and transplantation assays, we found that the inhibition of the transforming growth factor-β (TGF-β) pathway promoted the expansion of CD133-expressing PDECs for many generations and maintained the ability of CD133-expressing PDECs to generate insulin-producing cells. Moreover, western blot, qRT-PCR, and dual luciferase assays using TGF-β inhibitors were performed to identify the mechanisms by which TGF-β signaling regulates proliferation and differentiation. The results showed that the inhibition of TGF-β signaling enhancedId2binding to the promoter region of the cell proliferation repressorp16and promoted the expansion of CD133-expressing PDECs, and the increasedId2binding toNeuroD1decreased the transcription ofPax6to maintain CD133-expressing PDECs in the Pdx1-expression stage. Taken together, the effect of TGF-β antagonists on CD133-expressing PDECs reveals a novel paradigm of signaling that explains the balance between the expansion and differentiation of pancreatic duct epithelial progenitors.