A Critical Re-evaluation of "Bridging Single Cells to Organs: Mesoscale Modules as Fundamental Units of Tissue Function" by Chen et al., Cell 2025; doi: 10.1016/j.cell.2025.10.012

This deposit contains a Matters Arising–style critical commentary on the paper “Bridging Single Cells to Organs: Mesoscale Modules as Fundamental Units of Tissue Function” by Chen Y, Germain RN, Hunter GL, et al. (Cell, 2025). The commentary, authored by Yiheng Wang and Shu-Feng Zhou, evaluates the conceptual, methodological, computational, imaging, and interpretive foundations of the original study. The analysis highlights several key issues: the absence of a quantitative, operational definition of “mesoscale modules,” potential imaging and segmentation artifacts misinterpreted as biological structure, under-specified computational pipelines and lack of robustness testing, over-interpretation of developmental, cross-species, and cross-tissue similarities, inadequate and non-specific perturbation experiments, oversimplified mechanical and functional models not supported by causal evidence. The commentary provides a figure-by-figure critique covering all main Figures, Extended Data Figures, and Supplementary Figures. The purpose is constructive: to clarify methodological uncertainties, improve reproducibility, and encourage rigorous experimental validation before asserting a universal principle of mesoscale tissue modularity. This Zenodo record supports transparent post-publication peer review, academic discussion, and open scientific debate regarding the robustness, reproducibility, and interpretation of high-impact imaging-driven biological studies.