Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes.
Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes.
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DOI：
10.3389/fgene.2017.00035
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发表时间：
2017
影响因子：
3.7
通讯作者：
Stein RW
中科院分区：
文献类型：
--
作者：
Hunter CS;Stein RW
两种主要类型的糖尿病具有不同的病因，但结果相似：胰岛β细胞功能丧失，其仅负责分泌胰岛素激素以将升高的血糖降低至正常血糖水平。1型糖尿病（T1 D）传统上以自身免疫介导的β细胞死亡为特征，导致胰岛素依赖，而2型糖尿病（T2 D）具有外周胰岛素抵抗、β细胞功能障碍和细胞死亡的特征。然而，越来越多的证据表明，特别是在T2 D期间，β细胞衰竭的关键成分涉及：（1）细胞身份的丧失，特别是与成熟细胞功能相关的蛋白质（例如，胰岛素和转录因子如MAFA、PDX 1和NKX6.1），以及（2）去分化，其定义为退化至祖细胞或干细胞样状态。新技术使该领域能够通过单细胞RNA测序和表观遗传分析比较正常人类供体与病理生理条件下的胰岛细胞特征。这揭示了在组织学定义的“胰岛素阳性”β细胞之间的显著水平的异质性。这些结果不仅表明这些β细胞亚群对胰岛素促分泌素具有不同的反应，而且确定其独特的基因表达和表观遗传修饰谱将为开发细胞治疗剂提供机会，以富集/维持某些亚群，用于纠正病理性葡萄糖水平。在这篇综述中，我们将总结最近的文献，描述β细胞的异质性和可塑性可能会影响T2 D，以及各种可能的治疗干预途径。
The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e.g., insulin and transcription factors like MAFA, PDX1, and NKX6.1), as well as (2) de-differentiation, defined by regression to a progenitor or stem cell-like state. New technologies have allowed the field to compare islet cell characteristics from normal human donors to those under pathophysiological conditions by single cell RNA-Sequencing and through epigenetic analysis. This has revealed a remarkable level of heterogeneity among histologically defined “insulin-positive” β-cells. These results not only suggest that these β-cell subsets have different responses to insulin secretagogues, but that defining their unique gene expression and epigenetic modification profiles will offer opportunities to develop cellular therapeutics to enrich/maintain certain subsets for correcting pathological glucose levels. In this review, we will summarize the recent literature describing how β-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention.