The role of lung lipofibroblasts in alveolar differentiation

摘要 早产的一个并发症是肺发育不全，缺乏表面活性物质和足够的气体。 因肺泡未成熟而换血。尽管最近取得了进展，但这一进程 肺泡成熟还不是很清楚。本项目的一个目标是了解信令 来自引导肺泡生成的间充质细胞，肺发育的最后阶段。我们 发现破坏一种特殊的成纤维细胞，即脂成纤维细胞，会导致类型减少 肺泡细胞分化。II型肺泡细胞负责表面活性物质的产生， 我们还将研究肺组织中脂成纤维细胞和肺泡细胞之间的联系。 在老鼠体内发育。脂成纤维细胞一直是一个很难识别的细胞，而且几乎没有。 了解这些细胞的功能。我们的初步数据显示， 脂肪成纤维细胞的发育和肺泡分化所需的因子。基于 这些初步发现，我们假设脂成纤维细胞是需要的后续步骤 肺发育，并分泌终末期所需的生长因子 II型肺泡细胞的分化。我们将从两个方面研究这些细胞间的相互作用 明确的目标。在特定的目标I中，我们将确定脂成纤维细胞如何影响肺泡 通过检测脂成纤维细胞的时间需求和评估进行分化 缺乏脂成纤维细胞的小鼠的出生后肺发育。在特定目标II中，我们将在 体外器官培养和基因表达谱研究脂成纤维细胞信号 直接导致II型肺泡分化。这些目标加在一起将定义 脂成纤维细胞和潜在的增加II型肺泡率的治疗靶点的确定 早产儿的分化。

Abstract A complication of preterm birth is underdeveloped lungs that lack surfactant and adequate gas exchange due to immature alveoli. Although recent advances have been made, the process of alveolar maturation is not well understood. A goal of this project is to understand signaling from mesenchymal cells that direct alveologenesis, the final stage of lung development. We have found that disruption of a specialized fibroblast, the lipofibroblast, results in reduced type II alveolar cell differentiation. Type II alveolar cells are responsible for surfactant production, and we will investigate the communication between lipofibroblasts and alveolar cells during lung development in the mouse. The lipofibroblast has been a difficult cell to identify, and little is known about the function of these cells. Our preliminary data demonstrate that a transcription factor is required for the development of lipofibroblasts and alveolar differentiation. Based upon these preliminary findings, we hypothesize that lipofibroblasts are required for the later steps of lung development and that they secrete growth factors that are required specifically for terminal differentiation of type II alveolar cells. We will investigate these cellular interactions in two specific aims. In specific aim I, we will determine how lipofibroblasts impact alveolar differentiation by examining the temporal requirement for lipofibroblasts and by evaluating postnatal lung development in mice lacking lipofibroblasts. In Specific Aim II we will use in vitro organoid culture and gene expression profiling to explore the lipofibroblast cellular signals that direct type II alveolar differentiation. Together these aims will define the role of the lipofibroblast and potentially identify therapeutic targets for increasing the rate of type II alveolar differentiation in preterm births.