Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals

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. We leveraged spatial transcriptomics to overview molecular organization with anatomical divisions during cardiac regeneration. We collected a total of 19 specimens from 10 hearts at 8 developmental points, including seven P1 hearts post-AR (P1+1dpr-7dpr) and four hearts as controls (WT: P1, P7; and SH: P1+4,6 dps). Sample sections were collected with the maximum 4-chamber view along the dorsal-ventral axis, and the sectioning depth of individual hearts increased with postnatal days, reflecting an increase in dorsal-ventral dimensions as the heart grew and ensuring comparable histological views across samples. After data trimming for quality control, the joint dataset yielded a pool of 16,654 individual spots (average 5,343 genes per spot) and identified 16 clusters by uniform manifold approximation and projection (UMAP) corresponding to cardiac anatomical divisions in high spatial and molecular resolution, allowing us to study molecular diversity in intact tissue in space without bias.