Unraveling the spatial organization and development of human thymocytes through integration of spatial transcriptomics and single-cell multi-omics profiling
Yanchuan Li, Huamei Li, Cheng Peng, Ge Meng, Yijun Lü, H Liu, Cui Li, Huan Zhou, Zhu Xu, Lingyun Sun, Lihong Liu, Qing Xiong, Beicheng Sun, Shiping Jiao
Abstract
The structural components of the thymus are essential for guiding T cell development, but a thorough spatial view is still absent. Here we develop the TSO-his tool, designed to integrate multimodal data from single-cell and spatial transcriptomics to decipher the intricate structure of human thymus. Specifically, we characterize dynamic changes in cell types and critical markers, identifying ELOVL4 as a mediator of CD4+ T cell positive selection in the cortex. Utilizing the mapping function of TSO-his, we reconstruct thymic spatial architecture at single-cell resolution and recapitulates classical cell types and their essential co-localization for T cell development; additionally, previously unknown co-localization relationships such as that of CD8αα with memory B cells and monocytes are identified. Incorporating VDJ sequencing data, we also delineate distinct intermediate thymocyte states during αβ T cell development. Overall, these insights enhance our understanding of thymic biology and may inform therapeutic interventions targeting T cell-mediated immune responses. Thymus is important for shaping T cell immunity, but spatial insights at cellular and molecular level are still scarce. Here the author use multi-omics approaches and custom algorithms to reconstruct the spatial organization of human thymi for both confirming known features and unrevealing new components during thymocyte maturation.