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Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

ABSTRACT: The transport of gases, nutrients, metabolites and cells - a prerequisite for proper organogenesis and tissue homeostasis - requires a functional circulatory system consisting of arteries and veins, separated by intervening capillary networks. Despite their shared origin and some common functions, endothelial cells (ECs), which line every blood vessel, display profound structural and functional heterogeneity unique to the organ and tissue that they reside in. The diversity of phenotypes that ECs can adopt suggest substantial plasticity and indicates that heterogeneity is a core endothelial property that allows ECs to fulfill their multiple tasks. While the anatomical heterogeneity of blood vessels across different organs has been appreciated for centuries, the molecular basis of the variation within the vertebrate vascular tree is poorly understood. To decipher the transcriptional and epigenetic basis of endothelial heterogeneity across organs, and to determine how ECs mature during development, we surveyed the transcriptional and accessible chromatin landscape of ECs from the brain, retina, heart, liver, lung, and kidney of E12.5, P6, and adult mice. Through analysis of differential gene expression signatures, as well as chromatin accessibility, we have identified unique transcripts, as well as regulatory regions, that define each organ bed and developmental time point. Additionally, through single cell RNA-seq profiling of the embryonic and adult mouse we have determined that the endothelium of a single organ - in this case the brain - uses a diverse set of gene regulatory networks to mature and create a functional blood brain barrier.

ORGANISM(S): Mus musculus

PROVIDER: GSE185345 | GEO | 2022/07/01

REPOSITORIES: GEO

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Project description:An early aspect of sepsis is dysregulated activation of endothelial cells (EC), initiating a cascade of inflammatory signaling leading to leukocyte adhesion/migration and organ damage. Therapeutic targeting of ECs has been hampered by concerns regarding ECs heterogeneity from different organs. Using a combination of in vitro and in silico analysis, we present a comprehensive analysis of proteomic changes in mouse lung, kidney and liver ECs following exposure to a clinically relevant cocktail of proinflammatory cytokines. Mouse lung, liver and kidney ECs were incubated with TNFα/IL-1β/IFNγ for 4 or 24 hrs to model inflammatory responses during sepsis. Quantitative label-free global proteomics was performed on the ECs to identify differentially expressed proteins (DEP). Proteins with an abundance ratio >2.0 or <0.5 and an adjusted p<0.05 were characterized as upregulated or downregulated respectively. Gene Ontology (GO) classification was used to determine biological processes that regulate EC function during sepsis and PANTHER was used to classify the molecular function of the identified proteins. Finally, an interactive pathway was developed to investigate signaling within ECs and across organs. Proteomic analysis identified both unique and shared DEPs between the ECs specific to lung, liver and kidney. Using GO, 5 Biological Processes (BP) for each of the organ specific ECs were identified. Interestingly, 4 of the top 5 GO BPs were observed in all 3 ECs at 4 and 24 hrs: defense response to other organism, innate immune response, response to bacterium and response to cytokine. However, these BPs were found to be differentially regulated. For example, at 4 and 24 hrs, lung ECs which have the highest number and highest fold expression of upregulated proteins (189 and 316 respectively), also have higher numbers of unique upregulated proteins (124 vs 194) compared to liver (98 vs 121) and kidney ECs (109 vs 136). The liver showed the greatest number of conserved proteins between 4 and 24 hrs (56) compared to lung (50) and kidney (51). The number of common proteins between all three ECs increases from 38 at 4 hrs to 79 at 24 hrs, indicating more uniformity in ECs proteomic expression during the progression of sepsis. The PANTHER database was used to classify proteins in different functional groups (e.g. defense/immunity) at 4 and 24 hrs. Thus, BPs and PANTHER hits can provide insight into why some organs are more susceptible to sepsis early on and show that as sepsis progresses, some protein expression patterns become more uniform while additional organ specific proteins are expressed. Proteomic analysis of organ-specific ECs provides further understanding of how sepsis affects multiple organs across time and supports future proteomic, temporal studies of EC dysfunction.

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Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

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