Identification of proliferative and mature β-cells in the islets of Langerhans
Identification of proliferative and mature β-cells in the islets of Langerhans
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DOI：
10.1038/nature18624
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发表时间：
2016-07-21
期刊：
影响因子：
64.8
通讯作者：
Lickert, Heiko
中科院分区：
文献类型：
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作者：
Bader, Erik;Migliorini, Adriana;Lickert, Heiko
胰岛素依赖型糖尿病是一种复杂的多因素疾病，其特征在于β细胞的损失或功能障碍。胰腺β细胞在大小、葡萄糖反应性、胰岛素分泌和前体细胞潜力方面不同（1-5）;了解这种功能异质性的机制可能使开发新的再生方法成为可能。在这里，我们表明Fltp（也称为Flattop和Cfap 126），一种Wnt/平面细胞极性（PCP）效应子和报告基因（6），作为一种标记基因，将内分泌细胞细分为两个亚群，并以不同的分子，生理和超微结构特征区分有增殖能力的成熟β细胞。遗传谱系追踪显示，Fltp阴性和阳性谱系的内分泌亚群对生理和病理变化的反应不同。当内分泌细胞聚集在一起形成极化和成熟的3D胰岛小器官时，Fltp的表达增加（7-9）。我们表明，3D结构和Wnt/PCP配体足以触发β细胞成熟。相比之下，Wnt/PCP效应因子Fltp对于β细胞发育、增殖或成熟不是必需的。我们的结论是，三维结构和Wnt/PCP信号转导功能β细胞异质性的基础，并诱导β细胞成熟。Fltp作为内分泌亚群标志物的鉴定揭示了胰岛细胞异质性和可塑性的分子基础，并可能使靶向内分泌亚群用于糖尿病患者功能性β细胞群的再生。
Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential(1-5); understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene(6), acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature beta-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs(7-9). We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger beta-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for beta-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional beta-cell heterogeneity and induce beta-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional beta-cell mass in diabetic patients.