Defining the Pancreatic Progenitor Mesenchymal Niche

描述（由申请人提供）：最近对成人组织特异性祖细胞的兴趣激增，强化了祖细胞从未自主功能的原则；它们的行为总是由它们独特的空间位置发出的信号所控制。将这一原理应用于胰腺，我们提出胰腺干细胞/祖细胞的成功靶向治疗需要对其相应的间充质生态位进行有效的表征和操作。因此，我们提出了一个创新的、高度整合的研究项目，以识别、表征和操纵成人和胚胎胰腺中的胰腺祖细胞间充质生态位。该建议是基于我们最近在成年小鼠胰腺中发现的低丰度、自我更新的多系上皮祖细胞群，以及能够促进祖细胞扩增的相应间充质生态位细胞。基于这些令人兴奋的发现，我们提出以下中心假设：第一，胚胎和成年小鼠胰腺存在独特的间充质生态位细胞群。其次，生态位鉴定是由特定可溶性形态因子的产生和分泌来确定的。第三，对生态位细胞“分泌组”的描述将允许识别特定的形态原

DESCRIPTION (provided by applicant): The recent explosion of interest in adult tissue-specific progenitor cells has reinforced the principle that progenitor cells never function autonomously; their behavior is always governed by signals emanating from their unique spatial niche. Translating this principle to the pancreas, we propose that successful therapeutic targeting of pancreatic stem/progenitor cells will require effective characterization and manipulation of their corresponding mesenchymal niche. We are therefore proposing an innovative and highly integrated research program to identify, characterize and manipulate the pancreatic progenitor mesenchymal niche in adult and embryonic pancreas. The proposal is based on our recent identification of both a low-abundance, self-renewing, multi-lineage epithelial progenitor cell population in adult mouse pancreas, and a corresponding mesenchymal niche cell capable of promoting progenitor expansion. Based on these exciting findings, we are proposing the following central hypotheses: First, that unique population of mesenchymal niche cells exist embryonic and adult mouse pancreas. Second, that niche identify is defined by the production and secretion of specific soluble morphogens. Third, that characterization of the niche cell "secretome" will allow the identification of specific morphogens responsible for regulating the proliferation, differentiation and self-renewal of embryonic and adult pancreatic progenitor cells. To test these hypotheses, we are proposing three Specific Aims. Specific Aims 1 and 2 share parallel approaches applied to the embryonic pancreas in Aim 1 and to normal and regenerating adult pancreas in Aim 2. For both of these Aims, we will characterize and quantify the relative abundance of different pancreatic mesenchymal cell subpopulations, test their ability to regulate the proliferative expansion, differentiation and sel-renewal of pancreatic epithelial progenitor cells, and identify relevant components of the niche "secretome" responsible for these effects. Having identified specific niche cell populations and associated secreted morphogens responsible for niche function, experiments in Aim 3 will seek to genetically manipulate adult pancreatic mesenchymal niche cells, using a combination of Cre/lox and rtTA/TRE technology for mesenchyme-specific, doxycycline-inducible expression of ActivinA and other secreted morphogens. Together, these Aims will provide an entirely novel and integrated view of pancreatic mesenchymal development and pancreatic niche biology, setting the stage for eventual therapeutic manipulation of the adult pancreatic progenitor mesenchymal niche.