Transforming growth factor β is a critical regulator of adult human islet plasticity
Transforming growth factor β is a critical regulator of adult human islet plasticity
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DOI：
10.1210/me.2007-0045
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发表时间：
2007-06-01
影响因子：
--
通讯作者：
Rosenberg, Lawrence
中科院分区：
文献类型：
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作者：
Hanley, Stephen;Rosenberg, Lawrence
组织可塑性在胰腺再生和癌发生的背景下已有充分记录，最近的报告表明去分化的胰岛细胞既是内分泌祖细胞，又是胰腺腺癌的起源细胞。因此，值得注意的是，越来越多的证据表明，TGFβ信号传导对于胰腺内分泌的发育和维持至关重要，而其缺失则与胰腺癌的进展相关。本研究的目的是检查 TGF β 在胰岛形态发生可塑性体外模型中的作用。将人类胰岛嵌入胶原凝胶中，并在诱导转化为导管样上皮结构 (DLS) 的条件下进行培养。添加 TGF β 导致 DLS 形成呈剂量依赖性减少。尽管已证明胶原蛋白包埋的胰岛分泌低水平的 TGF β，但抗体介导的内源释放 TGF β 的中和提高了 DLS 形成率，表明局部 TGF β 浓度实际上可能更高。时程研究表明，TGF β 信号传导与 ERK 和 p38 MAPK 磷酸化的增加相关，尽管基于抑制剂的研究与 p38 单独介导的胰岛内分泌稳定作用一致。 TGFβ信号分子的定位表明TGFβ的作用直接作用于β细胞以抑制细胞凋亡，从而稳定内分泌表型。
Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGF beta signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGF beta in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGF beta caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGF beta, antibody-mediated neutralization of this endogenously released TGF beta improved DLS formation rates, suggesting local TGF beta concentrations may in fact be higher. Time course studies indicated that TGF beta signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGF beta signaling molecules suggested that the action of TGF beta is directly on the beta-cell to inhibit apoptosis and thus stabilize endocrine phenotype.