Resident Progenitor Cells in the Adventitia

描述(申请人提供)：该项目的长期目标是确定调节外膜发育和功能的细胞和分子机制，外膜是动脉壁的一层重要但知之甚少的层。我们最近在发育中的导管动脉和静脉中发现了一个Sonic Hedgehog(Shh)信号域，该信号域仅定位于外膜，含有常驻的Sca1+祖细胞(AdvSca1)。在脊椎动物中，HH蛋白是一种形态原，它激活平滑(SMO)依赖的信号通路，形成结缔组织，控制动静脉识别，并指导谱系特异性干细胞/祖细胞的生长和生存功能。在血管系统中，外膜在动脉壁内稳态和疾病中起着重要作用。外膜含有血管微血管，这些微血管是白细胞进出动脉粥样硬化病变的关键通道。此外，血管壁重塑、动脉张力和顺应性以及血管周围脂肪组织都严重依赖于外膜。大多数形式的动脉损伤都会引起快速而强烈的外膜反应，这表明感知和响应损伤的细胞和分子途径是外膜细胞的内在功能。我们已发表的和初步的数据确定了常驻Shh依赖的祖细胞群体，该细胞群体在应对多种形式的血管损伤时被动员起来。我们使用ShhEGFP/+报告鼠的初步研究表明，外膜中Shh的主要生产者是AdvSca1细胞本身。相比之下，Gli1lacZ/+、Ptc1lacZ/+和Ptc2lacZ/+报告小鼠表明，外膜中大多数Shh反应细胞是CD68+、F4/80+和CSF1R+常驻巨噬细胞样细胞(AdvRM)。AdvRM细胞聚集在靠近或直接接触内外膜的AdvSca1细胞。这些结果提高了这部小说的地位 通过AdvSca1前体细胞和AdvRms之间的相互信号相互作用而形成和维持的内外膜中的前体细胞生态位的可能性。我们认为，外膜祖细胞壁龛内的细胞在中膜-外膜界面通过旁分泌信号通路启动代偿性壁重塑和修复反应。为了验证这一新的假设，我们将强调整体动物实验和体内遗传命运定位方法。这个项目的结果将改变我们目前对外膜在动脉壁发育、动态平衡和疾病中的作用的理解。

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify cellular and molecular mechanisms that regulate the development and function of the tunica adventitia, an important but poorly understood layer of artery wall. We recently discovered a sonic hedgehog (Shh) signaling domain in developing conduit arteries and veins that is localized exclusively to the adventitia and contains resident Sca1+ progenitor cells (AdvSca1). In vertebrates, Hh proteins are morphogens that activate smoothened (SMO)-dependent signaling pathways to pattern connective tissue, control arterial-venous identity, and direct growth and survival functions for lineage-specific stem/progenitor cells. In the vascular system, the adventitia plays important roles in artery wall homeostasis and disease. The adventitia contains vasa vasorum microvessels that are key conduits for leukocyte trafficking into and out of atherosclerotic lesions. In addition, vessel wall remodeling, arterial tone and compliance, and perivascular adipose tissue are all critically dependent on the adventitia. Most forms of arterial injury evoke rapid and robust adventitial reactions suggesting that cellular and molecular pathways that sense and respond to injury are intrinsic functions of adventitial cells. Our published and preliminary data identify a resident Shh- dependent progenitor cell population that is mobilized in response to multiple forms of vascular injury. Our preliminary studies using ShhEGFP/+ reporter mice suggest that the primary producers of Shh in the adventitia are AdvSca1 cells themselves. By contrast, Gli1lacZ/+, Ptc1lacZ/+, and Ptc2lacZ/+ reporter mice indicate that the majority of Shh-responsive cells in the adventitia are CD68+, F4/80+, and Csf1R+ resident macrophage-like cells (AdvRM). AdvRM cells are clustered in close proximity to, or in direct contact with, AdvSca1 cells in the inner adventitia. These results raise the novel possibility of a progenitor cell niche in the inner adventitia that is formed and maintained by reciprocal signaling interactions between AdvSca1 progenitor cells and AdvRMs. We propose that cells within the adventitial progenitor niche function at the media-adventitia interface to initiate compensatory wall remodeling and repair responses via paracrine signaling pathways in the vessel wall. To test this novel hypothesis, we will emphasize whole animal experiments and genetic fate mapping approaches in vivo. The results of this project will change our current understanding of the roles of the adventitia in development, homeostasis and disease of the artery wall.