Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling
Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling
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DOI：
10.1172/jci91761
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发表时间：
2017-10-02
影响因子：
15.9
通讯作者：
Powers, Alvin C.
中科院分区：
文献类型：
--
作者：
Dai, Chunhua;Hang, Yan;Powers, Alvin C.
胰腺 β 细胞功能不足是 1 型和 2 型糖尿病的基础。扩展功能细胞的策略集中于发现和控制限制人类β细胞增殖的机制。在这里，我们开发了一种植入策略来检查与年龄相关的人类胰岛细胞复制能力，并揭示人类胰岛中β细胞增殖随年龄而下降的潜在机制。我们发现 exendin-4 (Ex-4) 是胰高血糖素样肽 1 受体 (GLP-1R) 的激动剂，可刺激幼年胰岛而非成年胰岛中的人类 β 细胞增殖。这种年龄依赖性反应性并不反映成年胰岛中 GLP-1R 信号传导的丧失，因为 Ex-4 治疗刺激了青少年和成人β细胞的胰岛素分泌。我们发现 Ex-4 的促有丝分裂作用需要钙调神经磷酸酶/活化 T 细胞核因子 (NFAT) 信号传导。在幼年胰岛中，Ex-4 诱导钙调磷酸酶/NFAT 信号成分以及增殖促进因子靶基因（包括 NFATC1、FOXM1 和 CCNA1）的表达。相比之下，这些因子在成年胰岛β细胞中的表达不受Ex-4暴露的影响。这些研究揭示了调节人类β细胞增殖的年龄依赖性信号传导机制，并确定了可适用于人类β细胞治疗性扩增的元件。
Inadequate pancreatic beta cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human beta cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of beta cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human beta cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human beta cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet beta cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human beta cell proliferation, and identify elements that could be adapted for therapeutic expansion of human beta cells.