[논문공부] Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia (Nat Commun, 2022)

https://doi.org/10.1038/s41467-022-33202-2

 

Abstract

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.

🔥 논문요약
Hyperlipidemia 시에 면역세포, VIC(valvular interstitila cell), VEC(valvular enothelial cell)의 compositional 및 phenotypic 변화가 일어남을 확인함. Ldlr -/- (hyperliidemia 유도) mouse에서 pro-inflammatory MHCII high macrophage가 증가함. Cd36+ EC에서 PPARγ pathway activation 되면서 aortic valve의 monocyte와 macrophage 축적을 억제함.

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Results

Aorta cell type 구성정리

 

1. Immune cell (Macrophage, T cell, B cell, Dendritic cell)

🍎 Macrophage

• 이 논문에서는 가장 크게 MHCII hi, CD11C+ macrophage와 MHCII lo, CD206+ macrophage로 구분함. (아마 M1 like, M2 like로 묶일 것 같음)
• Single cell RNA sequencing 결과를 토대로 macrophage를 더 세분화해서 구분함.
• Cluster 마다 heterogeneity가 크다고 밝히면서, 총 5개의 cluster-specific expressed genes과 pathway를 보여줌.
• Trem2, Lpl, Fabp5 등의 gene을 발현하고 lipid handling pathway가 두드러지게 나타나는 cluster: foamy macrophage라고 함.
• Foamy macrophage: 거품 세포라고 불리며 지질을 포함하는 세포임. plaque를 형성하여 동맥경화증을 유발하고 심근경색과 뇌졸중을 일으킬 수 있다고 알려짐. M2-like macrophage로서 지방이 많음. LDL을 포함하고 있으며, 현미경으로 관찰하면 거품 모양의 형태를 띄고 있는 것을 볼 수 있음.

2. Endothelial cell (Cd36+ EC, Edn1+ EC, Prox1+ EC, Fgfr3+ EC, Pdpn+ EC, unknown)

• Cd36+ EC, Prox1+ EC, Fgfr3+ EC가 차지하는 비율이 가장 높음
• Hyperlipidemia 시, Cd36+ EC가 두드러지게 증가함.
• Prox1+ EC는 fibrosa side, Fgfr3+ EC는 ventricularis side에 위치하고, Cd36+ EC의 위치는 특정한 패턴이 없음.
• Public data를 토대로 subtype을 검증함. (Kalluri et al.)