Modularity-based mathematical modeling of ligand inter-nanocluster connectivity for unraveling reversible stem cell regulation

• Published in: Nature communications 2024-12, Vol.15 (1), p.10665-22, Article 10665
• Main Authors: Kim, Chowon, Kang, Nayeon, Min, Sunhong, Thangam, Ramar, Lee, Sungkyu, Hong, Hyunsik, Kim, Kanghyeon, Kim, Seong Yeol, Kim, Dahee, Rha, Hyunji, Tag, Kyong-Ryol, Lee, Hyun-Jeong, Singh, Nem, Jeong, Daun, Hwang, Jangsun, Kim, Yuri, Park, Sangwoo, Lee, Hyesung, Kim, Taeeon, Son, Sang Wook, Park, Steve, Karamikamkar, Solmaz, Zhu, Yangzhi, Hassani Najafabadi, Alireza, Chu, Zhiqin, Sun, Wujin, Zhao, Pengchao, Zhang, Kunyu, Bian, Liming, Song, Hyun-Cheol, Park, Sung-Gyu, Kim, Jong Seung, Lee, Sang-Yup, Ahn, Jae-Pyoung, Kim, Hong-Kyu, Zhang, Yu Shrike, Kang, Heemin
• Format: Article
• Language: English
• Subjects: 13/100; 13/107; 631/532; 631/61/2035; 639/166/985; 639/301/54; 639/925/350; Animals; Anisotropy; Aspartic acid; Cell Differentiation; Clusters; Connectivity; Dynamical systems; Extracellular matrix; Extracellular Matrix - metabolism; Glycine; Graph theory; Humanities and Social Sciences; Humans; Integrins - metabolism; Ligands; Mathematical models; Mechanotransduction; Mechanotransduction, Cellular; Mice; Models, Theoretical; Modularity; multidisciplinary; Nanoclusters; Oligopeptides - metabolism; Oligopeptides - pharmacology; Regeneration (physiology); Science; Science (multidisciplinary); Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Tissue engineering
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54557-8

The native extracellular matrix is continuously remodeled to form complex interconnected network structures that reversibly regulate stem cell behaviors. Both regulation and understanding of its intricate dynamicity can help to modulate numerous cell behaviors. However, neither of these has yet been achieved due to the lack of designing and modeling such complex structures with dynamic controllability. Here we report modularity-based mathematical modeling of extracellular matrix-emulating ligand inter-cluster connectivity using the graph theory. Increasing anisotropy of magnetic nano-blockers proportionately disconnects arginine-glycine-aspartic acid ligand-to-ligand interconnections and decreases the number of ligand inter-cluster edges. This phenomenon deactivates stem cells, which can be partly activated by linearizing the nano-blockers. Remote cyclic elevation of high-anisotropy nano-blockers flexibly generates nano-gaps under the nano-blockers and augments the number of ligand inter-cluster edges. Subsequently, integrin-presenting stem cell infiltration is stimulated, which reversibly intensifies focal adhesion and mechanotransduction-driven differentiation both in vitro and in vivo. Designing and systemically modeling extracellular matrix-mimetic geometries opens avenues for unraveling dynamic cell-material interactions for tissue regeneration. The extracellular matrix is remodeled to form complex interconnected network structures that regulate stem cell behaviors. Here, the authors modulate extracellular matrix-like networks using magnetic nano-blockers, adjusting stem cell behavior by changing ligand inter-cluster connectivity. This dynamic system provides new insights into cell-material interactions for tissue regeneration.