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. 2020 Sep:91-92:51-74.
doi: 10.1016/j.matbio.2020.05.002. Epub 2020 May 19.

The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration

Matthew Riccetti  1 , Jason J Gokey  2 , Bruce Aronow  3 , Anne-Karina T Perl  4
Affiliations

The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration

Matthew Riccetti et al. Matrix Biol. 2020 Sep.

Abstract

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.

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Figures

Figure 1-
Figure 1-. Location, Location, Location
Representational drawing of an adult donor lung histology section. Each of the eight functional mesenchymal subtypes found in the adult lung are located to their niche based on their lineage definition in the literature. The table includes accepted lineage labels currently available in the field.
Figure 2
Figure 2. Heatmap “Lineage Markers”:
Expression of established lineage markers in mesenchymal populations identified by single cell RNA-Seq heatmap: 14 of the 16 lineage markers were identified in the scRNA-seq dataset and displayed in a heatmap (Wt1, Ng2, Thy1, Lgr5 and Lgr6 were expressed at very low levels). The x-axis was arranged by cell type, cell subtype, and age group, respectively. Yellow represents high expression and black represents little to no expression.
Figure 3:
Figure 3:. Heatmap “Transcription factors”
Expression of transcription factors in mesenchymal populations identified by single cell RNA-Seq heatmap. These transcription factors are the highest expressed (TPM>2.5) and most specifically expressed within the mesenchymal population. Transcription factors were placed on the y-axis of a single cell RNA-seq heatmap. The x-axis was arranged by cell type, cell subtype, and age group, respectively. Yellow represents highest expression.
Figure 4:
Figure 4:. Heatmap “Sender-Ligands”
Expression of signaling pathway ligands in mesenchymal populations identified by single cell RNA-Seq heatmap: These ligands are the highest and most specifically expressed in the mesenchyme compared to all other cell types. Ligands were placed on the y-axis of a single cell RNA-seq heatmap. The x-axis was arranged by cell type, cell subtype, and age group, respectively. Yellow represents highest expression.
Figure 5:
Figure 5:. Heatmap “receiver-Receptors”
Expression of signaling pathway receptor in mesenchymal populations identified by single cell RNA-Seq heatmap: These receptors are the highest and most specifically expressed in the mesenchyme compared to all other cell types. Signaling pathway receptors were placed on the y-axis of a scRNA-seq heatmap. The x-axis was arranged by cell type, cell subtype, and age group, respectively. Yellow represents highest expression.
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