2. Academic Validation
  3. Stiff extracellular matrix drives the differentiation of mesenchymal stem cells toward osteogenesis by the multiscale 3D genome reorganization

Stiff extracellular matrix drives the differentiation of mesenchymal stem cells toward osteogenesis by the multiscale 3D genome reorganization

  • Biomaterials. 2024 Jul 27:312:122715. doi: 10.1016/j.biomaterials.2024.122715.
Jing Na 1,  Chengzheng Tai 1,  Ziyi Wang 1,  Zhijie Yang 1,  Xinyuan Chen 1,  Jing Zhang 2,  Lisha Zheng 3,  Yubo Fan 4
Affiliations

Affiliations

  • 1 Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
  • 2 Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China; Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, 100083, China. Electronic address: jz2716@buaa.edu.cn.
  • 3 Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China. Electronic address: lishazheng@buaa.edu.cn.
  • 4 Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China. Electronic address: yubofan@buaa.edu.cn.
PMID: 39094522 DOI: 10.1016/j.biomaterials.2024.122715
Abstract

Extracellular matrix (ECM) stiffness is a major driver of stem cell fate. However, the involvement of the three-dimensional (3D) genomic reorganization in response to ECM stiffness remains unclear. Here, we generated comprehensive 3D chromatin landscapes of mesenchymal stem cells (MSCs) exposed to various ECM stiffness. We found that there were more long-range chromatin interactions, but less compartment A in MSCs cultured on stiff ECM than those cultured on soft ECM. However, the switch from compartment B in MSCs cultured on soft ECM to compartment A in MSCs cultured on stiff ECM included genes encoding proteins primarily enriched in Cytoskeleton organization. At the topologically associating domains (TADs) level, stiff ECM tends to have merged TADs on soft ECM. These merged TADs on stiff ECM include upregulated genes encoding proteins enriched in osteogenesis, such as SP1, ETS1, and DCHS1, which were validated by quantitative real-time polymerase chain reaction and found to be consistent with the increase of Alkaline Phosphatase staining. Knockdown of SP1 or ETS1 led to the downregulation of osteogenic marker genes, including COL1A1, RUNX2, ALP, and OCN in MSCs cultured on stiff ECM. Our study provides an important insight into the stiff ECM-mediated promotion of MSC differentiation towards osteogenesis, emphasizing the influence of mechanical cues on the reorganization of 3D genome architecture and stem cell fate.

Keywords

3D genome; Extracellular matrix; Mesenchymal stem cells; Osteogenesis.

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