Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.
Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.
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DOI：
10.1016/j.stem.2021.08.003
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发表时间：
2021-11-04
期刊：
影响因子：
23.9
通讯作者：
Behrens A
中科院分区：
文献类型：
--
作者：
Gribben C;Lambert C;Messal HA;Hubber EL;Rackham C;Evans I;Heimberg H;Jones P;Sancho R;Behrens A
导管细胞被认为是成体β细胞新生的来源，但这仍然存在争议。通过结合谱系追踪，3D成像和单细胞RNA测序（scRNA-seq）方法，我们发现导管细胞随着时间的推移对β细胞群有贡献。使用神经生成素3（Ngn 3）-CreERT系的谱系追踪鉴定了表达内分泌主转录因子Ngn 3的导管细胞，其对δ细胞标志物生长抑素呈阳性，偶尔共表达胰岛素。在秋田+/−糖尿病小鼠中，表达ngn的导管细胞数量增加，ngn 3杂合性加速了糖尿病的发病。Ngn 3谱系示踪的胰岛细胞的scRNA-seq表明，导管来源的生长抑素表达细胞（其中一些保留导管标记物的表达）产生β细胞。这项研究确定Ngn 3表达导管细胞作为稳态和糖尿病中成体β细胞新生的来源，表明除了β细胞增殖之外，这种机制还维持了成体胰岛β细胞群。导管Ngn 3+细胞在体内平衡过程中对β细胞群有贡献导管驻留内分泌祖细胞表达生长抑素生长抑素阳性导管细胞在秋田+/−糖尿病小鼠中增加scRNA-seq分析表明导管生长抑素+细胞产生β细胞更好地理解成人β细胞新生将为糖尿病治疗开辟新途径。Gribben等人使用谱系追踪和scRNA-seq来表征导管驻留生长抑素阳性内分泌祖细胞群体，其是稳态和糖尿病期间β细胞的来源。
Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/− diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population. Ductal Ngn3+ cells contribute to the beta cell population during homeostasis Duct-resident endocrine progenitor cells express somatostatin Somatostatin-positive ductal cells are increased in Akita+/− diabetic mice scRNA-seq analysis suggests ductal somatostatin+ cells give rise to beta cells A better understanding of adult beta cell neogenesis would open new approaches for diabetes treatment. Gribben et al. used lineage tracing and scRNA-seq to characterize a duct-resident somatostatin-positive endocrine progenitor cell population that is a source of beta cells in homeostasis and during diabetes.
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