1Spatiotemporal transcriptomic atlas of atherosclerosis revealed Smooth muscle cells induce tertiary lymphoid organs in plaqueSource: STOmics DB (ID: STT0000052 )

Tertiary lymphoid organs (TLOs) develop within nonlymphoid tissues in response to persistent inflammation, However, there is limited knowledge regarding their presence in atherosclerosis diseases and the mechanisms underlying their development. Here, we used single-cell RNA sequencing and Spatial Enhanced Resolution Omics-sequencing (Stereo-seq) to obtain a comprehensive plaque atlas comprising 30 distinct transcriptome-defined cell types. Notably, we have observed the presence of TLOs within plaques, and their formation is closely associated with the expression of the lymphorganogenic chemokine, CXCL12, produced by fibroblast-like smooth muscle cells (SMCs) in a LTβR-dependent manner. In plaque TLOs (PTLOs), B cells were abundant and capable of differentiating into IgA- and IgG- plasma cells. BCR repertoire analysis unveiled clonal diversification, selection, expansion in PTLO, and the presence of identical B cell clonotypes in other regions of the plaques. Interestingly, we also identified the co-occurrence of unique B cell clonotypes in plaques and perivascular adipose tissue (PVAT) by using lineage analysis, indicating cell exchange between these compartments. PTLO-derived IgG antibodies promote the differentiation macrophages into foam cells, suggestive of pro-atherogenic effector activity. Additionally, the presence of PTLOs is linked with cardiovascular events. Thus, the PTLOs induced by fibroblast-like SMCs play key roles in the development and stability of atherosclerosis plaques, by conferring B cell maturation and IgG antibody production.