Myeloid cell regulation of adult lung alveologenesis post-pneumonectomy

肺切除术后成人肺泡生成的骨髓细胞调节

• 批准号: 9050115
• 负责人: Andrew John Lechner
• 金额: $ 3.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2018-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050115
• 关键词: Adult; Affect; Alveolar; Alveolus; Angiogenic Factor; Area; Behavior; Biological Assay; Blood Vessels; CCL2 gene; CSF1R gene; Cell Proliferation; Cells; Clinical; Colon; Data; Development; Distal; Endothelial Cells; Endothelium; Epithelial; Epithelium; Excision; Gases; Genetic; Goals; Growth; Heart; Human; Immune; Immunophenotyping; Infiltration; Kidney; Knockout Mice; Lead; Limb structure; Liver; Lobe; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Natural regeneration; Organ Donor; Pathway interactions; Patients; Peripheral; Play; Pneumonectomy; Population; Population Dynamics; Procedures; Recruitment Activity; Regulation; Reporter; Role; Signal Transduction; Skeletal Muscle; Skin; Spinal Cord; Staging; Stem cells; Structure of parenchyma of lung; Surface; Testing; Tissues; Vascular Endothelial Growth Factors; Virus; Wound Healing; angiogenesis; arginase; cell behavior; chemokine; injury and repair; loss of function; lung lobe; lung regeneration; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; novel; novel therapeutics; prevent; progenitor; public health relevance; regenerative; repaired; research study; stem cell niche; stem cell population; tissue regeneration; tissue repair; transcriptome sequencing

 DESCRIPTION (provided by applicant): The only available treatment for end stage lung diseases is a total lung transplant. This procedure is limited by poor survival and an inadequate supply of donor lungs. An alternative is to promote regeneration of normal lung tissue from endogenous progenitor cells. Partial pneumonectomy (PNX), the surgical removal of one or more lobes, stimulates compensatory lung growth in the remaining lobes in many mammalian species. This model of adult alveologenesis is mediated by proliferation of several progenitor populations, including alveolar epithelial type 2 cells (AEC2s), which are distal lung epithelial stem cells. Significant questions remain regarding the regenerative potential of human lungs, the identities of human lung epithelial stem cells, the molecular signals that control their activation, and the influences of the microenvironment on regeneration. Our objective is to apply data from murine studies to stimulate regeneration of human lungs. Recently macrophages have been implicated in tissue repair and regeneration, but little is know about their role in lung regeneration. We are using fluorescent reporters and genetic gain- and loss-of function in mice to identify populations of immune cells that modulate epithelial stem cell behaviors in adult lung regeneration. We will assess how macrophages may contribute to the regenerative niche of distal lung epithelial stem cells to promote adult alveologenesis post-PNX. We propose to first measure immune cell population dynamics and activation states post-PNX (Aim 1). Our preliminary data shows that that CD115+ myeloid cells increase in regenerating lung post-PNX and a subset of these cells co-express Arginase-1, a marker of M2-polarized macrophages shown previously to promote wound healing. We will further characterize the myeloid population dynamics post-PNX and determine if these cells increase by local proliferation or are derived from circulating monocytes. We will then test the requirement for macrophages in PNX-induced lung regeneration (Aim 2). Interestingly, the chemokine CCL2 is upregulated in lung epithelium post-PNX. We will disrupt CCL2 in the epithelium or its cognate receptor, CCR2, and determine how this impairs lung regeneration. Finally, our preliminary data suggests post-PNX macrophages secrete factors that could promote angiogenesis. We will investigate whether macrophages directly influence AEC2 proliferation post-PNX or if they indirectly influence AEC2 by promoting angiogenesis, which is required for PNX-induced lung regeneration (Aim 3). We will determine if endothelial proliferation is impaired in CCR2 knock-out mice and identify macrophage-specific pro-angiogenic pathways. We hope to identify mechanisms that mediate these effects that might be exploited to stimulate lung regeneration and may be developed into novel therapies for patients with end-stage lung disease.

 描述（由申请人提供）：终末期肺部疾病的唯一可用治疗方法是全肺移植。这种手术受到存活率低和供体肺供应不足的限制。另一种方法是促进正常肺组织从内源性祖细胞再生。部分肺切除术（PNX），手术切除一个或多个肺叶，刺激许多哺乳动物物种中剩余肺叶的代偿性肺生长。这种成人肺泡发生模型由几种祖细胞群的增殖介导，包括肺泡上皮2型细胞（AEC 2），其是远端肺上皮干细胞。关于人肺的再生潜力，人肺上皮干细胞的身份，控制其激活的分子信号以及微环境对再生的影响，仍然存在重大问题。 我们的目标是应用来自小鼠研究的数据来刺激人肺的再生。近年来巨噬细胞参与组织修复和再生，但对它们在肺再生中的作用知之甚少。我们正在使用荧光报告基因和遗传功能的获得和丧失来鉴定调节成人肺再生中上皮干细胞行为的免疫细胞群体。我们将评估巨噬细胞如何有助于远端肺上皮干细胞的再生生态位，以促进PNX后的成人肺泡形成。 我们建议首先测量免疫细胞群体动态和PNX后的激活状态（目的1）。我们的初步数据显示，CD 115+骨髓细胞在PNX后再生肺中增加，并且这些细胞的一个亚群共表达精氨酸酶-1，这是先前显示促进伤口愈合的M2极化巨噬细胞的标志物。我们将进一步描述PNX后的骨髓细胞群动态，并确定这些细胞是否通过局部增殖增加或来源于循环单核细胞。然后，我们将测试巨噬细胞在PNX诱导的肺再生中的需求（目的2）。有趣的是，趋化因子CCL 2在PNX后的肺上皮中上调。我们将破坏上皮细胞中的CCL 2或其同源受体CCR 2，并确定这如何损害肺再生。最后，我们的初步数据表明，后PNX巨噬细胞分泌的因子，可以促进血管生成。我们将研究巨噬细胞是否直接影响PNX后的AEC 2增殖，或者它们是否通过促进血管生成间接影响AEC 2，这是PNX诱导的肺再生所需的（目的3）。我们将确定CCR 2基因敲除小鼠的内皮细胞增殖是否受损，并确定巨噬细胞特异性促血管生成途径。 我们希望确定介导这些效应的机制，这些机制可能被用来刺激肺再生，并可能被开发为终末期肺病患者的新疗法。