Heterogeneous Responses of Human Aortic Endothelial Cells to Perturbations

核心概念

The author explores the heterogeneity of human aortic endothelial cells in response to various perturbations, highlighting distinct subtypes and their unique reactions. The study reveals that different perturbations have varied effects on different endothelial cell populations.

要約

The study delves into the heterogeneity of human aortic endothelial cells (HAECs) through multiomic profiling, identifying four major clusters with distinct pathway enrichment profiles. Exposure to different perturbations elicited unique transcriptional and chromatin responses in specific EC populations. Surprisingly, the mesenchymal population was minimally affected by canonical 'healthy' EC perturbations, suggesting stable molecular phenotypes in culture. The findings suggest that EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles.

統計

"Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles."
"HAEC cultures were reproducibly populated by 4 major clusters with distinct pathway enrichment profiles."
"Exposure to siERG, IL1B or TGFB2 elicited mostly distinct transcriptional and accessible chromatin responses."

引用

抽出されたキーインサイト

Single cell ‘omic profiles of human aortic endothelial cells in vitro and human atherosclerotic lesions ex vivo reveals heterogeneity of endothelial subtype and response to activating perturbations

by Adelus,M. L.... 場所 www.biorxiv.org 04-06-2023

https://www.biorxiv.org/content/10.1101/2023.04.03.535495v3

深掘り質問

What factors might contribute to the stability of molecular phenotypes in cultured HAECs despite exposure to perturbations

The stability of molecular phenotypes in cultured HAECs despite exposure to perturbations can be influenced by several factors. One key factor is the inherent heterogeneity within the cell population itself. The presence of distinct subtypes, such as EC1, EC2, EC3, and EC4 identified in this study, suggests that these cells may have different baseline molecular profiles that dictate their responses to perturbations. These stable molecular phenotypes could be a result of epigenetic modifications or regulatory networks that maintain cellular identity even when exposed to external stimuli.
Additionally, the microenvironment in which the cells are cultured plays a significant role in maintaining stability. Factors such as growth media composition, oxygen levels, and interactions with other cell types present in the culture system can all contribute to preserving specific molecular signatures within the cell populations.
Furthermore, genetic background and donor variability may also impact the stability of molecular phenotypes. The use of primary cultures from multiple donors allowed for an assessment of how genetic differences influence cellular responses to perturbations. Consistent findings across different donors suggest robustness and stability in certain aspects of cellular behavior.
Overall, a combination of intrinsic cellular characteristics, environmental cues, and genetic influences likely contributes to the maintenance of stable molecular phenotypes in cultured HAECs.

How could lineage tracing techniques enhance our understanding of the origin and behavior of mesenchymal-like cells within EC populations

Lineage tracing techniques could provide valuable insights into the origin and behavior of mesenchymal-like cells within EC populations. By tracking the lineage history of individual cells over time or under specific conditions using genetic markers or reporters, researchers can determine whether mesenchymal-like cells arise from endothelial cells through processes like EndMT or if they represent a separate cell population altogether.
Through lineage tracing experiments combined with single-cell sequencing technologies like those used in this study on human aortic endothelial cells (HAECs), researchers can identify transitional states between endothelial and mesenchymal fates more definitively. This approach would allow for precise mapping of cell transitions during disease progression such as atherosclerosis development.
Moreover, lineage tracing can help elucidate whether mesenchymal-like cells observed within EC populations are actively contributing to disease pathogenesis or if they represent quiescent or transient states without functional implications. Understanding the dynamics and plasticity between different cell states within vascular tissues could lead to novel therapeutic strategies targeting specific cellular transitions involved in disease progression.
In summary, lineage tracing techniques offer a powerful tool for unraveling complex cellular behaviors and origins within heterogeneous cell populations like those found among endothelial cells undergoing transition towards mesenchymal phenotypes.

How might the findings from this study impact future research on atherosclerosis progression and treatment strategies

The findings from this study have significant implications for future research on atherosclerosis progression and treatment strategies:

Improved In Vitro Modeling: The identification of distinct subpopulations among HAECs highlights the importance of considering heterogeneity when studying vascular diseases like atherosclerosis. Future studies can leverage this knowledge to develop more sophisticated in vitro models that better recapitulate diverse endothelial responses seen during disease progression.

Targeted Therapies: Understanding how pro-EndMT perturbations affect different EC subtypes provides insights into potential therapeutic targets for modulating pathological changes associated with atherosclerosis development.

Precision Medicine Approaches: By linking CAD-associated SNPs with specific epigenetic landscapes unique to certain EC subtypes (e.g., enrichment observed particularly in EC4), personalized treatment strategies targeting these pathways could be developed based on individual genetic risk profiles.

4Advancing Disease Mechanisms: Further exploration into how various activating environments influence gene expression patterns across heterogeneous endothelial populations will deepen our understanding not only about EndMT but also about broader mechanisms underlying cardiovascular diseases.
5Translational Impact: Translating these research findings into clinical applications may lead to innovative diagnostic tools capable fo identifying early-stage changes indicative fo increased cardiovascular risk due ot altered endotheial function
By integrating multiomic approaches with advanced computational analyses adn ex vivo validation studiesm future investigations ca further elucidate teh complexitiesof endotheial heterogenietyin relationto athrosclerossiand pave th wayfor novel therapeutic interventionsaimed at mitigating cardiovasculardiseaseprogression