During lung development, the mesenchyme and epithelium are dependent on each other for instructive morphogenic cues that direct proliferation, cellular differentiation and organogenesis. Specification of epithelial and mesenchymal cell lineages occurs in parallel, forming cellular subtypes that guide the formation of both transitional developmental structures and the permanent architecture of the adult lung. While epithelial cell types and lineages have been relatively well-defined in recent years, the definition of mesenchymal cell types and lineage relationships has been more challenging. Transgenic mouse lines with permanent and inducible lineage tracers have been instrumental in identifying lineage relationships among epithelial progenitor cells and their differentiation into distinct airway and alveolar epithelial cells. Lineage tracing experiments with reporter mice used to identify fibroblast progenitors and their lineage trajectories have been limited by the number of cell specific genes and the developmental timepoint when the lineage trace was activated. In this review, we discuss major developmental mesenchymal lineages, focusing on time of origin, major cell type, and other lineage derivatives, as well as the transgenic tools used to find and define them. We describe lung fibroblasts using function, location, and molecular markers in order to compare and contrast cells with similar functions. The temporal and cell-type specific expression of fourteen “fibroblast lineage” genes were identified in single-cell RNA-sequencing data from LungMAP in the LGEA database. Using these lineage signature genes as guides, we clustered murine lung fibroblast populations from embryonic day 16.5 to postnatal day 28 (E16.5-PN28) and generated heatmaps to illustrate expression of transcription factors, signaling receptors and ligands in a temporal and population specific manner.

在肺发育过程中，间充质和上皮细胞相互依赖以提供指导增殖、细胞分化和器官发生的指导性形态发生线索。上皮细胞和间充质细胞谱系的规范同时发生，形成细胞亚型，指导成人肺的过渡发育结构和永久结构的形成。尽管近年来上皮细胞类型和谱系已经相对明确，但间充质细胞类型和谱系关系的定义更具挑战性。具有永久和可诱导谱系示踪剂的转基因小鼠系有助于识别上皮祖细胞之间的谱系关系及其分化为不同的气道和肺泡上皮细胞。用于鉴定成纤维细胞祖细胞及其谱系轨迹的报告小鼠谱系追踪实验受到细胞特异性基因数量和谱系追踪激活时的发育时间点的限制。在这篇综述中，我们讨论了主要的发育间充质谱系，重点关注起源时间、主要细胞类型和其他谱系衍生物，以及用于查找和定义它们的转基因工具。我们使用功能、位置和分子标记来描述肺成纤维细胞，以便比较和对比具有相似功能的细胞。LGEA 数据库中 LungMAP 的单细胞 RNA 测序数据确定了 14 个“成纤维细胞谱系”基因的时间和细胞类型特异性表达。使用这些谱系特征基因作为指导，