2. Academic Validation
  3. Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway

Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway

  • Acta Biomater. 2023 Jul 17;S1742-7061(23)00396-3. doi: 10.1016/j.actbio.2023.07.012.
Ting Jiang 1,  Xin-Yue Tang 1,  Yi Mao 2,  Yu-Qi Zhou 3,  Jia-Jia Wang 2,  Ruo-Mei Li 1,  Xin-Ru Xie 2,  Hong-Ming Zhang 3,  Bing Fang 4,  Ning-Juan Ouyang 5,  Guo-Hua Tang 6
Affiliations

Affiliations

  • 1 Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai, 200011, People's Republic of China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China.
  • 2 Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai, 200011, People's Republic of China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China.
  • 3 Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China.
  • 4 Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai, 200011, People's Republic of China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China. Electronic address: fangbing@sjtu.edu.cn.
  • 5 Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai, 200011, People's Republic of China. Electronic address: oynjc0508@163.com.
  • 6 Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology. Shanghai, 200011, People's Republic of China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China. Electronic address: drtanggh@163.com.
PMID: 37467837 DOI: 10.1016/j.actbio.2023.07.012
Abstract

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less Reactive Oxygen Species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA Sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE: : • The 3D culture system was more suitable for neutrophils (Neus), providing an opportunity to mimic the in-vivo experiments. • Substrate stiffness could alter neutrophil phenotypes and stiffer substrate promoted Neus to shift to the N2 phenotype, which was regulated by modulating the JAK1/STAT3 pathway. • This work lays the foundation for the application of hydrogel-based biomaterials, which provides more treatment options for ischemic diseases and bone defects.

Keywords

Angiogenesis; Matrix mechanics; Neutrophil; Polarization; Substrate stiffness.

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