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Kinetics and genomic profiling of adult human and mouse β-cell maturation

机译：成年人和小鼠β细胞成熟的动力学和基因组分析

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Diabetes is a multifactorial metabolic disorder defined by the loss of functional pancreatic insulin-producing β-cells. The functional maturation and dedifferentiation of adult β-cells is central to diabetes pathogenesis and to β-cell replacement therapy for the treatment of diabetes. Despite its importance, the dynamics and mechanisms of adult β-cell maturation remain poorly understood. Using a novel Pdx1/Ins1 dual fluorescent reporter lentiviral vector, we previously found that individual adult human and mouse β-cells exist in at least two differentiation states distinguishable by the activation of the rat Ins1 promoter and performed the first real-time imaging of the maturation of individual cultured β-cells. Our previous study focused on transformed (MIN6) β-cells as a model to investigate the kinetics of β-cell maturation. In the present study, we investigated the kinetics of the maturation process in primary human and mouse β-cells and performed gene expression profiling. Gene expression profiling of FACS purified immature Pdx1 +/Ins1 low cells and mature Pdx1 high/Ins1 high cells from cultures of human islets, mouse islets and MIN6 cells revealed that Pdx1 +/Ins1 low cells are enriched for multiple genes associated with β-cell development/ progenitor cells, proliferation, apoptosis, as well as genes coding for other islet cell hormones such as glucagon. We also demonstrated that the heterogeneity in β-cell maturation states previously observed in vitro, can also be found in vivo. Collectively, these experiments contribute to the understanding of maturation, dedifferentiation and plasticity of adult pancreatic β-cells. The results have significant implications for islet regeneration and for in vitro generation of functional β-cells to treat diabetes.
机译：糖尿病是由功能性胰腺产生胰岛素的β细胞丧失定义的多因素代谢紊乱。成人β细胞的功能成熟和去分化对于糖尿病的发病机制以及治疗糖尿病的β细胞替代疗法至关重要。尽管它的重要性，成人β细胞成熟的动力学和机制仍然知之甚少。使用新颖的Pdx1 / Ins1双荧光报告基因慢病毒载体，我们先前发现，成年的人类和小鼠β细胞至少存在两种​​可通过大鼠Ins1启动子激活区分开的分化状态，并对其进行了首次实时成像。单个培养的β细胞的成熟。我们先前的研究集中在转化的（MIN6）β细胞作为研究β细胞成熟动力学的模型上。在本研究中，我们研究了原代人和小鼠β细胞中成熟过程的动力学，并进行了基因表达谱分析。从人胰岛，小鼠胰岛和MIN6细胞的培养物中FACS纯化的未成熟Pdx1 + / Ins1低细胞和成熟Pdx1 high / Ins1高细胞的基因表达谱分析显示，Pdx1 + / Ins1低细胞富含与β细胞相关的多个基因发育/祖细胞，增殖，凋亡以及编码其他胰岛细胞激素（例如胰高血糖素）的基因。我们还证明，先前在体外观察到的β细胞成熟状态的异质性也可以在体内发现。总的来说，这些实验有助于理解成年胰腺β细胞的成熟，去分化和可塑性。该结果对胰岛再生和用于治疗糖尿病的功能性β细胞的体外产生具有重要意义。

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