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The Lung Microenvironment Instructs Gene Transcription in Neonatal and Adult Alveolar Macrophages

ABSTRACT: Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. Here we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs. While the core AM signature was similar, adult AMs expressed higher levels of genes involved in lipid metabolism, while neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by ATAC-seq contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-kB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonates and adults, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal AMs retained high expression of some proinflammatory genes, suggesting the differences in neonatal AMs result from both inherent cell properties and environmental influences.

ORGANISM(S): Mus musculus

PROVIDER: GSE196926 | GEO | 2022/07/05

REPOSITORIES: GEO

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Project description:The lower glucose-responsiveness of neonatal beta cells is generally considered a sign of endocrine immaturity. We compared mRNA profiles of neonatal and 10-weeks old rat beta cells to see how their gene expression changes with functional maturation. Neonatal beta cells showed a lower glucose-inducible increment in insulin production than adult cells. This was in part explained by basal protein synthetic hyperactivity of neonatal cells: while at 2.5mM glucose 80% of neonatal beta cells were recruited into active protein synthesis, 10 mM glucose was required to achieve a similar fraction of active adult beta cells. Besides this progressive recruitment, glucose exerted in both age groups an additional amplifying effect in the recruited cells, but clearly more so in adult beta cells that showed a higher maximal synthetic capacity/cell. Neonatal beta cells balanced an advanced endocrine differentiation as judged by their mRNA expression of conserved beta cell marker genes, with higher expression of genes involved in cell cycle and development. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset, as marked by high DLK1. Neonatal pancreas contained distinct subsets of DLK1high and DLK1low insulin-expressing cells, but both showed equal hyperactivity. We conclude that neonatal beta cells combine advanced endocrine maturation with traits of residual developmental immaturity. If DLK1 is used as marker for the latter, the basal hyperactivity which proved to be a cardinal feature of neonatal beta cells is not a direct reflection of their residual immaturity. A genome-wide view on postnatal maturation/differentiation of the rat beta cells The study compares Affymetrix RG230.20 expression profiles of 3 cell subsets: (1) HSSC: a population of cells isolated from post natal day 2-3 rat pancreas that is enriched (65-70%) in insulin cells (n=3), (2) LSSC: a population of cells isolated from postnatal day 2-3 rat pancreas that is mostly devoid of endocrine cells, and selected by its low side scatter (n=3); and (3) adult beta: a reference population of FACS-purified adult rat beta cells (>90% insulin+) freshly isolated from pancreas of 10 weeks-old rats (n=5). RNA was extracted from the cells immediately after isolation, without further treatment or culture. Details of the isolation procedure and extensive microscopic characterization of the preps are described in the accompanying scientific paper by Martens GA et al.

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The Lung Microenvironment Instructs Gene Transcription in Neonatal and Adult Alveolar Macrophages

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