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Modulate spatial restriction of injury responses for cardiac repair

ABSTRACT: Intrinsic molecular strategy at the organ level to injury stimuli remains elusive. Identifying and modulating such potential molecular strategy for systemic adaptations to injury is theoretically fascinating and therapeutically promising. Here, using integrative single-cell and spatial transcriptomic analysis, we reported that lysozyme 2 (Lyz2), a long-established myeloid marker, surprisingly indicated global injury status (across cell types and anatomic divisions) and influenced cardiac function after injury. We correlated the Lyz2 regulon of the lysosome-matrisome (particularly endocardial lysosomal-degrading Hspgs) with anatomical and functional relevance to cardiac injury and determined that such spatial model is consensus across various injury types, both mouse and human. Modulation of spatial model mediated by Lyz2 via genetic deletion or chemical inhibition in adult mice with myocardial infarction remarkably achieved immediate protective effects, a rare therapeutic benefit among current interventions for heart failure. These results provided the first molecular evidence for the unprecedented molecular strategy adopted by the heart with unparalleled therapeutic promising for organ repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE247626 | GEO | 2025/09/29

REPOSITORIES: GEO

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Project description:Background: Sepsis can lead to multiple organ damage, and the heart is one of the most vulnerable organs. Vagal nerve stimulation can reduce myocardial injury in sepsis and improve survival rate. However, the relative effect of disparate cell populations on sepsis induced myocardial dysfunction and the low-level tragus stimulation on it, remain unclear. Methods: We used the cardiac single-cell transcriptomic strategy to characterize the cardiac cell population and the network of cells that forms the heart. And we selected all cardiac macrophage from CD45+ cells using single-cell mRNA sequencing data. Then we used echocardiography performing, western blot and immunofluorescence and immunohistochemical technology to verify the data of the single-cell mRNA sequencing results. Results: In single-cell mRNA sequencing data, our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to sepsis induced myocardial dysfunction under low-level tragus stimulation. Pseudo timing analysis in single-cell sequencing showed that low level vagal nerve stimulation could induce the transformation of cardiac monocytes into M2 macrophages and play an anti-inflammatory role. After low-level tragus stimulation, the expression of α7nAChR in the heart tissue increased significantly. Echocardiography showed that low-level tragus stimulation could improve the cardiac function of septic myocardial injury of the mice. Comparing with the sepsis group, the expression of interleukin-1β in heart tissue of the mice in sepsis with low-level tragus stimulation group is significantly lower. Conclusion: Low-level tragus stimulation can improve sepsis-induced myocardial dysfunction by promoting cardiac monocytes to M2 macrophages. Goal of the study: In the present study, we aimed to screen macrophages, their crosstalk with other cells, and macrophages associated with cardiac injury and further verify their origins and roles in the septic myocardial injury process and low-level tragus stimulation (LL-TS) to treat septic myocardial dysfunction.

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Modulate spatial restriction of injury responses for cardiac repair

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