Significance of stereologically spatiotemporal cells in molecular medicine

Abstract

Spatiotemporal distributions of intracellular elements (e.g., small molecules, proteins and organelles) dynamically altered in response to extracellular stimuli and pathogens, regulating those element movements, remodelling, and functions independently of mere changes in element abundance. To distinguish from conventional one- or two-dimensional spatialization, we define the precise three-dimensional localisation and interactions of intra- and extracellular elements at the single cell level as the “stereologically spatiotemporal cell” (SST-cell). For example, the three-dimensional construction of chromosomes ensures their proper formation and spatial positioning, facilitates the recruitment of regulatory factors, and underlies the mechanisms by which these factors maintain chromatin architecture. A large number of intracellular organelles and sub-organelles, along with their intercommunications, decide cellular biological types, subtype specification and type-specific functions. With the development of Stereo-Cell and Stereo-seq, the measurement of spatial SST-cell omics probably enables the detailed dissection of spatial heterogeneity among different cell subtypes and states, as well as their intercellular communications. Furthermore, the new approach of single SST-cell drug screening will be innovated for developing the new generation of clinical precision therapies.

Keywords

organelles / single-cell / spatialization / stereology / temporalization

References

[1] Hein MY, Peng D, Todorova V, et al. Global organelle profiling reveals subcellular localization and remodeling at proteome scale. Cell. 2025; 188(4): 1137-1155. e20.

[2] Martinez-Val A, Bekker-Jensen DB, Steigerwald S, et al. Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution. Nat Commun. 2021; 12: 7113.

[3] Wang X, Duan W, Liu X, Fan J. An important step to translate single-cell measurement into clinical practice: stereoscopic cells. Clin Transl Med. 2025; 15: e70304.

[4] Li KR, Yu PL, Zheng QQ, et al. Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution. Cell. 2025; 188(3): 24.

[5] Chen A, Liao S, Cheng M, et al. Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays. Cell. 2022; 185(10): 1777-1792.e21.

[6] Zhao H, Shu L, Qin S, et al. Extensive mutual influences of SMC complexes shape 3D genome folding. Nature. 2025; 640(8058): 543-553.

[7] Sebastian R, Sun EG, Fedkenheuer M, et al. Mechanism for local attenuation of DNA replication at double-strand breaks. Nature. 2025; 639(8056): 1084-1092.

[8] Wu H, Zhang J, Jian F, et al. Simultaneous single-cell three-dimensional genome and gene expression profiling uncovers dynamic enhancer connectivity underlying olfactory receptor choice. Nat Methods. 2024; 21(6): 974-982.

[9] Takei Y, Yang Y, White J, et al. Spatial multi-omics reveals cell-type-specific nuclear compartments. Nature. 2025; 641(8064): 1037-1047.

[10] Merta H, Gov K, Isogai T, et al. Spatial proteomics of ER tubules reveals CLMN, an ER-actin tether at focal adhesions that promotes cell migration. Cell Rep. 2025; 44(4): 115502.

[11] Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature. 2018; 554(7692): 382-386.

[12] Xiao Z, Cui L, Yuan Y, He N, Xie X, Lin S, et al. 3D reconstruction of a gastrulating human embryo. Cell. 2024; 187(11): 2855-2874.e19.

[13] Schott M, León-Periñán D, Splendiani E, et al. Open-ST: high-resolution spatial transcriptomics in 3D. Cell. 2024; 187(15): 3953-3972.e26.

[14] Yayon N, Kedlian VR, Boehme L, et al. A spatial human thymus cell atlas mapped to a continuous tissue axis. Nature. 2024; 635(8039): 708-718.

[15] Mathur R, Wang Q, Schupp PG, et al. Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective. Cell. 2024; 187(2): 446-463.e16.

[16] Mo CK, Liu J, Chen S, et al. Tumour evolution and microenvironment interactions in 2D and 3D space. Nature. 2024; 634(8036): 1178-1186.

[17] Liao S, Zhou X, Liu C, et al. Stereo-cell: spatial enhanced-resolution single-cell sequencing with high-density DNA nanoball-patterned arrays. Science. 2025; 389(6762): eadr0475.

[18] Han M, Fu ML, Zhu Y, et al. Programmable control of spatial transcriptome in live cells and neurons. Nature. 2025; 643(8070): 241-251.

[19] Trendel J, Trendel S, Sha S, et al. The human proteome with direct physical access to DNA. Cell. 2025; 188(16): S0092-8674(25)00507-0.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.