Department of Biosignals and Inheritance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; Division of Biomedical Engineering for Health and Welfare, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
Department of Advanced Transdisciplinary Sciences, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
J Lipid Res. 2024 Sep;65(9):100620. doi: 10.1016/j.jlr.2024.100620. Epub 2024 Aug 14.
Adipose tissue remodeling and plasticity are dynamically regulated by the coordinated functions of adipocytes, macrophages, and endothelial cells and extracellular matrix (ECM) that provides stiffness networks in adipose tissue component cells. Inflammation and fibrosis are crucial exogenous factors that dysregulate adipose tissue functions and drastically change the mechanical properties of the ECM. Therefore, communication among the ECM and adipose tissue component cells is necessary to understand the multifaceted functions of adipose tissues. To obtain in vivo stiffness, we used genipin as a crosslinker for collagen gels. Meanwhile, we isolated primary adipocytes, macrophages, and endothelial cells from C57BL/6J mice and incubated these cells in the differentiation media on temperature-responsive culture dishes. After the differentiation, these cell sheets were transferred onto genipin-crosslinked collagen gels with varying matrix stiffness. We found that inflammatory gene expressions were induced by hard matrix, whereas antiinflammatory gene expressions were promoted by soft matrix in all three types of cells. Interestingly, the coculture experiments of adipocytes, macrophages, and endothelial cells showed that the effects of soft or hard matrix stiffness stimulation on adipocytes were transmitted to the distant adipose tissue component cells, altering their gene expression profiles under normal matrix conditions. Finally, we identified that a hard matrix induces the secretion of CXCL13 from adipocytes, and CXCL13 is one of the important transmitters for stiffness communication with macrophages and endothelial cells. These findings provide insight into the mechanotransmission into distant cells and the application of stiffness control for chronic inflammation in adipose tissues with metabolic dysregulation.
脂肪组织重塑和可塑性是由脂肪细胞、巨噬细胞和内皮细胞以及细胞外基质（ECM）的协调功能动态调节的，ECM 为脂肪组织成分细胞提供了僵硬的网络。炎症和纤维化是失调脂肪组织功能并显著改变 ECM 力学特性的关键外源性因素。因此，了解 ECM 和脂肪组织成分细胞之间的通讯对于理解脂肪组织的多方面功能是必要的。为了获得体内的硬度，我们使用京尼平作为胶原凝胶的交联剂。同时，我们从 C57BL/6J 小鼠中分离出原代脂肪细胞、巨噬细胞和内皮细胞，并将这些细胞在温度响应培养皿中的分化培养基中孵育。分化后，这些细胞片被转移到具有不同基质硬度的京尼平交联胶原凝胶上。我们发现，硬基质诱导了所有三种细胞的炎症基因表达，而软基质则促进了抗炎基因表达。有趣的是，脂肪细胞、巨噬细胞和内皮细胞的共培养实验表明，软或硬基质硬度刺激对脂肪细胞的影响传递到远处的脂肪组织成分细胞，在正常基质条件下改变了它们的基因表达谱。最后，我们确定硬基质诱导脂肪细胞分泌 CXCL13，而 CXCL13 是与巨噬细胞和内皮细胞进行刚度通讯的重要递质之一。这些发现为深入了解机械信号传递到远处细胞以及通过控制硬度来应用于代谢失调的脂肪组织中的慢性炎症提供了思路。
