A novel progenitor population in pancreatic endocrine cell development

胰腺内分泌细胞发育中的新型祖细胞群

基本信息

项目摘要

Endocrine cells in the pancreas synthesize and secrete hormones required for energy homeostasis and nutrient metabolism. In particular, insulin-producing beta cells are required to control systemic blood glucose levels, and their loss or dysfunction leads to diabetes. The endocrine cells that make up pancreatic islets form during development from the differentiation of endocrine precursors, or pro-endocrine cells. Although all five endocrine lineages derive from a common pool of endocrine precursors, how these pro-endocrine cells become committed to a particular endocrine cell subtype is poorly understood. A more detailed molecular characterization of the precise stages of differentiation from an endocrine precursor to a differentiated endocrine cell is needed. During pancreatic organogenesis, a subset of cells in the ductal epithelium transiently expresses Neurogenin3 (Ngn3), a pro-endocrine transcription factor that is required for endocrine lineage specification. Lineage tracing has demonstrated that all five endocrine lineages are derived from these Ngn3-expressing precursors, and that Ngn3-expressing cells do not give rise to other pancreatic lineages besides endocrine. It is not yet determined if each Ngn3(+) cell is pre-committed to a specific endocrine lineage or if cell fate decisions are made at a later stage, after Ngn3 expression. Using single-cell RNA sequencing (RNA-seq) of murine pancreata, our laboratory has identified a novel cell population that expresses endocrine lineage genes and is defined by differential expression of the transcription factor Fev. This FevHI population is also characterized by lack of expression of Ngn3(+) or of the pancreatic hormones detected in differentiated endocrine cells. Lineage tracing of Ngn3-expressing cells in vivo has revealed that Fev-expressing cells are descendants of Ngn3(+) pro-endocrine cells. Thus, this novel putative endocrine precursor population appears to represent an intermediate stage following transient Ngn3 expression and before hormone acquisition. The experiments outlined in this proposal begin with a focus on characterizing the spatial and temporal appearance of this novel FevHI population in human fetal and adult pancreata. In addition, genetic lineage tracing studies will be undertaken to define the downstream lineage of this putative FevHI intermediate precursor. Lastly, as Fev whole body knockout mice display defects in glucose homeostasis, the role of FEV itself in endocrine cell specification and functional maturation of human beta cells will be investigated using a human embryonic stem cell-based platform and genomic engineering strategies. The overarching goal of these studies is both to provide new insights into the basic biology underlying endocrine cell fate allocation, as well as to harness this knowledge for generating functional human embryonic stem cell-derived beta cells and regenerating endogenous beta cells for the treatment of diabetes.
胰腺中的内分泌细胞合成和分泌能量稳态和营养代谢所需的激素。特别是,需要产生胰岛素的β细胞来控制全身血糖水平,它们的损失或功能障碍会导致糖尿病。组成胰岛的内分泌细胞是在发育过程中由内分泌前体细胞或前内分泌细胞分化形成的。尽管所有五种内分泌谱系都源自共同的内分泌前体细胞库,但人们对这些前内分泌细胞如何转变为特定的内分泌细胞亚型仍知之甚少。需要对从内分泌前体细胞分化为分化内分泌细胞的精确分化阶段进行更详细的分子表征。 在胰腺器官发生过程中,导管上皮中的一部分细胞短暂表达 Neurogenin3 (Ngn3),这是一种内分泌谱系规范所需的前内分泌转录因子。谱系追踪表明,所有五种内分泌谱系均源自这些表达 Ngn3 的前体细胞,并且表达 Ngn3 的细胞不会产生除内分泌谱系之外的其他胰腺谱系。目前尚不清楚每个 Ngn3(+) 细胞是否预先定型为特定的内分泌谱系,或者细胞命运的决定是否是在 Ngn3 表达后的后期阶段做出的。 利用小鼠胰腺的单细胞 RNA 测序 (RNA-seq),我们的实验室鉴定出了一种表达内分泌谱系基因的新细胞群,并由转录因子 Fev 的差异表达来定义。该 FevHI 群体的特征还在于缺乏 Ngn3(+) 或在分化的内分泌细胞中检测到的胰腺激素的表达。体内 Ngn3 表达细胞的谱系追踪表明,Fev 表达细胞是 Ngn3(+) 前内分泌细胞的后代。因此,这种新的假定的内分泌前体群体似乎代表了瞬时 Ngn3 表达之后和激素获得之前的中间阶段。 本提案中概述的实验首先重点描述人类胎儿和成人胰腺中这种新型 FevHI 群体的空间和时间外观。此外,还将进行遗传谱系追踪研究,以确定这种假定的 FevHI 中间体前体的下游谱系。最后,由于 Fev 全身基因敲除小鼠表现出葡萄糖稳态缺陷,因此将使用基于人类胚胎干细胞的平台和基因组工程策略来研究 FEV 本身在内分泌细胞规范和人类 β 细胞功能成熟中的作用。这些研究的总体目标是为内分泌细胞命运分配的基础生物学提供新的见解,并利用这些知识来生成功能性人胚胎干细胞衍生的β细胞和再生内源性β细胞以治疗糖尿病。

项目成果

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Julie Beth Sneddon其他文献

Julie Beth Sneddon的其他文献

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{{ truncateString('Julie Beth Sneddon', 18)}}的其他基金

A novel progenitor population in pancreatic endocrine cell development
胰腺内分泌细胞发育中的新型祖细胞群
  • 批准号:
    10253286
  • 财政年份:
    2019
  • 资助金额:
    $ 40.38万
  • 项目类别:
A novel progenitor population in pancreatic endocrine cell development
胰腺内分泌细胞发育中的新型祖细胞群
  • 批准号:
    10597993
  • 财政年份:
    2019
  • 资助金额:
    $ 40.38万
  • 项目类别:

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