Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
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DOI：
10.1016/j.cmet.2017.01.009
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发表时间：
2017-03-07
期刊：
影响因子：
29
通讯作者：
Kim SK
中科院分区：
文献类型：
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作者：
Chakravarthy H;Gu X;Enge M;Dai X;Wang Y;Damond N;Downie C;Liu K;Wang J;Xing Y;Chera S;Thorel F;Quake S;Oberholzer J;MacDonald PE;Herrera PL;Kim SK
小鼠中产生胰岛素的胰腺β细胞可以在β细胞丢失等情况下从产生胰高血糖素的α细胞缓慢再生，但这种转化的基础尚不清楚。此外，尚不清楚这种胰岛内细胞转化是否与1型糖尿病（T1 D）等疾病有关。我们发现α细胞调节因子Aristaless-related homeobox（Arx）和DNA甲基转移酶1（Dnmt 1）维持小鼠α细胞的同一性。在Dnmt 1和Arx缺失的3个月内，谱系追踪和单细胞RNA测序显示α细胞广泛转化为类似于天然β细胞的后代。生理学研究表明，转化的α-细胞获得标志性β-细胞电生理学，并显示葡萄糖刺激的胰岛素分泌。在T1 D患者中，表达胰高血糖素的细胞亚群显示DNMT 1和ARX的缺失，并产生胰岛素和其他β细胞因子，表明DNMT 1和ARX在人体中保持α细胞特性。我们的工作揭示了Arx和Dnmt 1调节的途径，足以实现从成人胰腺α细胞靶向生成β细胞。
Insulin-producing pancreatic β-cells in mice can slowly regenerate from glucagon-producing α-cells in settings like β-cell loss, but the basis of this conversion is unknown. Moreover it remains unclear if this intra-islet cell conversion is relevant to diseases like type 1 diabetes (T1D). We show that the α-cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain α-cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single cell RNA sequencing revealed extensive α-cell conversion into progeny resembling native β-cells. Physiological studies demonstrated that converted α-cells acquire hallmark β-cell electrophysiology, and show glucose-stimulated insulin secretion. In T1D patients, subsets of Glucagon-expressing cells show loss of DNMT1 and ARX, and produce Insulin and other β-cell factors, suggesting that DNMT1 and ARX maintain α-cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 sufficient for achieving targeted generation of β-cells from adult pancreatic α-cells.