Chakravarthy Harini, Gu Xueying, Enge Martin, Dai Xiaoqing, Wang Yong, Damond Nicolas, Downie Carolina, Liu Kathy, Wang Jing, Xing Yuan, Chera Simona, Thorel Fabrizio, Quake Stephen, Oberholzer Jose, MacDonald Patrick E, Herrera Pedro L, Kim Seung K
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16.
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 that are sufficient for achieving targeted generation of β cells from adult pancreatic α cells.
在诸如β细胞缺失等情况下，小鼠中产生胰岛素的胰腺β细胞可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，胰岛内细胞转化是否与1型糖尿病（T1D）等疾病相关仍不明确。我们发现，α细胞调节因子无尾相关同源框（Arx）和DNA甲基转移酶1（Dnmt1）可维持小鼠的α细胞身份。在Dnmt1和Arx缺失的3个月内，谱系追踪和单细胞RNA测序显示，大量α细胞转化为类似天然β细胞的后代。生理学研究表明，转化后的α细胞获得了典型的β细胞电生理特性，并表现出葡萄糖刺激的胰岛素分泌。在T1D患者中，表达胰高血糖素的细胞亚群显示DNMT1和ARX缺失，并产生胰岛素和其他β细胞因子，这表明DNMT1和ARX在人类中维持α细胞身份。我们的研究揭示了由Arx和Dnmt1调控的途径，这些途径足以实现从成年胰腺α细胞靶向生成β细胞。
