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Human and murine transcriptome profiling identifies cross-species homology in pulmonary mononuclear phagocytes [DCs and Monocytes]

ABSTRACT: The mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells. MP subtypes play distinct functional roles in steady-state and inflammatory conditions. Though murine MPs are well characterized, their human homologues remain poorly understood, particularly in the lung and draining lymph nodes (LNs). Understanding these homologies, and their similarities and differences with murine MPs, is critical for identifying human genetic targets and thus developing human immunotherapies. To address this gap, we performed transcriptome-based alignment across fifteen distinct human and nine distinct murine lung and LN MPs. As controls to validate the analytical quality of cross-species pulmonary MP analysis, human blood and murine spleen MPs were used. Constrained canonical correlation, t-SNE and catplot visualization was used to align human and mouse MPs and identify MP subtypes with maximal correspondence across species. Among the top marker genes expressed in corresponding human-mouse MP pairs, only 30-10% of the genes overlapped, indicating a need for caution when identifying human gene variants and functions from mice. For instance, SPP1 is highly expressed in human interstitial macrophages but not alveolar macrophages (AMs), whereas in mice SSP1 is only expressed in AMs. Moreover, human LN dendritic cells (DCs) align best with murine LN DCs but not murine splenic DCs indicating cross-species similarity in tissue. Lastly, in both species, CD88 was the most useful cell surface marker for distinguishing monocyte/macrophages from DCs. Overall, these data provide a reference for analyzing cross-species transcriptome data and evaluating whether specific murine genes are suitable guides to identify the functionality of human MPs, or conversely, whether pursuing specific human genes in mice, is likely to be a valid and fruitful approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE132911 | GEO | 2019/06/19

REPOSITORIES: GEO

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Project description:Tissue macrophages (MPs) develop distinctive functions due to unique transcriptional programs driven by local environmental ques. In the intestine, it is known that MPs are heterogeneous cells that differentiate from blood monocytes and embryonic precursors, and are essential for homeostasis with the vast microbiome through their ability to kill invading microbes, clear apoptotic cells, and produce regulatory cytokines. However, the full extent of MP heterogeneity, their developmental relationships, and how the intestinal microbiota affects MP generation is not known. Here, we performed single cell RNA sequencing of colonic myeloid cells from specific pathogen free (SPF) and germ free (GF) C57BL/6 mice and found extensive heterogeneity of colon MP, with at least six different identifiable populations, with less heterogeneity of dendritic cells (DCs). Unsupervised modeling of developmental pathways combined with inference of gene regulatory networks suggested two major trajectories from common CCR2+ precursors resulting in CD11c+CD9+MMRintCD121b+ and CD11c-CD9intMMRhiCD121b- MP populations with unique transcription factors activities to coordinate downstream target molecules. The generation of both mature populations of colon MPs was impaired in germ-free mice, which coincided with the appearance of a dominant unique population of MPs, whereas the generation of DC populations in GF mice were unaffected or increased. Furthermore, the two major MP populations were clearly distinct from other populations regarding their gene expression profile, localization within the lamina propria, and ability to phagocytose macromolecules from the blood. These data uncover the diversity of intestinal myeloid cell populations, highlight the importance of microbiota on the unique developmental as well as anatomical and functional fates of colon MPs. We anticipate that these findings will form the basis for future studies on how tissue myeloid cell development is influenced either directly or indirectly by signals from endogenous microbiota in the intestine, as well as other tissues.

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Human and murine transcriptome profiling identifies cross-species homology in pulmonary mononuclear phagocytes [DCs and Monocytes]

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