Non-Contact Transspatial Regulatory Function of the Extracellular Matrix

Abstract

As a crucial biological material, the extracellular matrix (ECM) constitutes a major part of the extracellular microenvironment, offering both structural support and essential biological signals to surrounding cells. Research into ECM properties not only deepens our understanding of cellular behavior and metabolism but also opens new avenues for studying disease mechanisms and therapies. In this work, we report a previously unrecognized function of ECM by leveraging a three-dimensional spatial cavity structure. It is termed “Non-contact Transspatial Regulatory” (nCTR), referring to the ECM that remotely regulates cells without traditional direct physical contact. Systematic investigation and validation of key factors reveal that nCTR strongly depends on the 3D spatial distance between ECM and cells, governed by both physical spatial confinement and chemical signaling exchange. The process involves multiple components, pathways, and mechanisms, with macropinocytosis playing a dominant role. This newly identified function of the ECM offers a fresh perspective on cellular behavior and will undoubtedly open a new frontier in the cellular microenvironment studies.

Keywords

extracellular matrix / macropinocytosis / non-contact / remote regulatory

References

[1] N. K. Karamanos, A. D. Theocharis, Z. Piperigkou, et al., “A Guide to the Composition and Functions of the Extracellular Matrix,” FEBS Journal 288 (2021): 6850–6912.

[2] D. A. C. Walma and K. M. Yamada, “The Extracellular Matrix in Development,” Development 147 (2020): dev175596.

[3] A. Saraswathibhatla, D. Indana, and O. Chaudhuri, “Cell-Extracellular Matrix Mechanotransduction in 3D,” Nature Reviews Molecular Cell Biology 24 (2023): 495–516.

[4] S. E. Murthy, A. E. Dubin, and A. Patapoutian, “Piezos Thrive Under Pressure: Mechanically Activated Ion Channels in Health and Disease,” Nature Reviews Molecular Cell Biology 18 (2017): 771–783.

[5] H. P. Lee, R. Stowers, and O. Chaudhuri, “Volume Expansion and TRPV4 Activation Regulate Stem Cell Fate in Three-Dimensional Microenvironments,” Nature Communications 10 (2019): 529.

[6] E. Entcheva and M. W. Kay, “Extracellular Matrix Components Halt Peripheral Nerve Regeneration After Myocardial Infarction,” American Journal of Physiology—Heart and Circulatory Physiology 327 (2024): H965–H966.

[7] G. E. Arteel, “Hepatic Extracellular Matrix and Its Role in the Regulation of Liver Phenotype,” Seminars in Liver Disease 44 (2024): 343–355.

[8] M. R. Chastney, J. Kaivola, V. M. Leppänen, and J. Ivaska, “The Role and Regulation of Integrins in Cell Migration and Invasion,” Nature Reviews Molecular Cell Biology 26 (2025): 147–167.

[9] J. J. F. Sleeboom, G. S. van Tienderen, K. Schenke-Layland, L. J. W. van der Laan, A. A. Khalil, and M. M. A. Verstegen, “The Extracellular Matrix as Hallmark of Cancer and Metastasis: From Biomechanics to Therapeutic Targets,” Science Translational Medicine 16 (2024): eadg3840.

[10] Q. Fan, Y. Zheng, X. Wang, et al., “Dynamically Re-Organized Collagen Fiber Bundles Transmit Mechanical Signals and Induce Strongly Correlated Cell Migration and Self-Organization,” Angewandte Chemie International Edition 60 (2021): 11858–11867.

[11] C. Yang, X. Wang, R. Xie, et al., “Dynamically Reconstructed Collagen Fibers for Transmitting Mechanical Signals to Assist Macrophages Tracing Breast Cancer Cells,” Advanced Functional Materials 33 (2023): 2211807.

[12] R. Xie, X. Yu, T. Cao, et al., “Fibrous Viscoelastic Extracellular Matrix Assists Precise Neuronal Connectivity,” Advanced Functional Materials 33 (2023): 2301926.

[13] S. M. Haake, B. L. Rios, A. Pozzi, and R. Zent, “Integrating Integrins With the Hallmarks of Cancer,” Matrix Biology 130 (2024): 20–35.

[14] J. Xiong, R. Xiao, J. Zhao, et al., “Matrix Stiffness Affects Tumor-Associated Macrophage Functional Polarization and Its Potential in Tumor Therapy,” Journal of Translational Medicine 22 (2024): 85.

[15] J. Schindelin, I. Arganda-Carreras, E. Frise, et al., “Fiji: An Open-Source Platform for Biological-Image Analysis,” Nature Methods 9 (2012): 676–682.

[16] D. Ershov, M. S. Phan, J. W. Pylvänäinen, et al., “Trackmate 7: Integrating State-Of-The-Art Segmentation Algorithms Into Tracking Pipelines,” Nature Methods 19 (2022): 829–832.

[17] H. Liu, Y. Wang, K. Cui, Y. Guo, X. Zhang, and J. Qin, “Advances in Hydrogels in Organoids and Organs-On-A-Chip,” Advanced Materials 31 (2019): 1902042.

[18] Z. Meng, Y. Zhang, L. Yang, et al., “Application of Advanced Biosensors in Nervous System Diseases,” Interdisciplinary Medicine 2 (2024): e20240024.

[19] COMSOL Multiphysics® v. 6.4. COMSOL AB, Stockholm, Sweden, 2025, www.comsol.com.

[20] Y. Chen, L. Chen, A. T. L. Lun, P. L. Baldoni, and G. K. Smyth, “Edger v4: Powerful Differential Analysis of Sequencing Data With Expanded Functionality and Improved Support for Small Counts and Larger Datasets,” Nucleic Acids Research 53 (2025): gkaf018.

[21] S. A. Aleksander, J. Balhoff, S. Carbon, et al., “The Gene Ontology Knowledgebase in 2023,” Genetics 224 (2023): iyad031.

[22] M. Kanehisa and S. Goto, “KEGG: Kyoto Encyclopedia of Genes and Genomes,” Nucleic Acids Research 28 (2000): 27–30.

[23] A. Subramanian, P. Tamayo, V. K. Mootha, et al., “Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles,” Proceedings of the National Academy of Sciences 102 (2005): 15545–15550.

[24] D. Szklarczyk, R. Kirsch, M. Koutrouli, et al., “The STRING Database in 2023: Protein-Protein Association Networks and Functional Enrichment Analyses for Any Sequenced Genome of Interest,” Nucleic Acids Research 51 (2023): D638–D646.

[25] R. Neupane, S. Malla, C. Karthikeyan, et al., “Endocytic Highways: Navigating Macropinocytosis and Other Endocytic Routes for Precision Drug Delivery,” International Journal of Pharmaceutics 673 (2025): 125356.

[26] K. Nakamura, A. R. Dalal, N. Yokoyama, et al., “Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-v Antagonism Reduces Aortic Root Aneurysm Formation in Marfan syndrome Mice,” Arteriosclerosis, Thrombosis, and Vascular Biology 43 (2023): 1134–1153.

[27] C. Tu, Z. Du, H. Zhang, et al., “Endocytic Pathway Inhibition Attenuates Extracellular Vesicle-Induced Reduction of Chemosensitivity to Bortezomib in Multiple Myeloma Cells,” Theranostics 11 (2021): 2364–2380.

[28] J. Wu, Y. Wang, Y. Wang, et al., “Interplay Between Extracellular Vesicles and Allergic Diseases: Current Insights and Future Perspectives,” Interdisciplinary Medicine 3 (2025): e20240049.

[29] H. Liang, X. Luo, Q. Lin, et al., “EIPA, a Macropinocytosis Blocking Agent, Inhibits Siniperca chuatsi Rhabdovirus Infection In Vitro and In Vivo,” Microbial Pathogenesis 206 (2025): 107751.

[30] Y. Wang, K. Zhang, Y. Ma, et al., “Liquid–Cell Interactions in the Tumor Microenvironment: Mechanisms, Biomarkers, and Therapeutic Opportunities,” Cellular Reprogramming, ahead of print, May 26, 2026, https://doi.org/10.1177/21524971261453859.

[31] X. Liu, Y. Ye, Z. Li, L. Liao, and Q. Wei, “Mechanical Rejuvenation of Senescent Stem Cells and Aged Bone via Chromatin Remodeling,” Nature Communications 17 (2026): 1684.

[32] Z. Piperigkou, S. Mangani, N. E. Koletsis, et al., “Principal Mechanisms of Extracellular Matrix-Mediated Cell–Cell Communication in Physiological and Tumor Microenvironments,” FEBS Journal 293 (2026): 26–41.

Rights & permissions

2026 The Author(s). Smart Medicine published by Wiley-VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.