Qin Aiping, Chen Sheng, Wang Ping, Huang Xiaotao, Zhang Yu, Liang Lu, Du Ling-Ran, Lai De-Hua, Ding Li, Yu Xiyong, Xiang Andy Peng
Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
Front Cell Dev Biol. 2021 Mar 19;9:638518. doi: 10.3389/fcell.2021.638518. eCollection 2021.
Mesenchymal stromal cells (MSCs) are a heterogeneous population of cells that possess multilineage differentiation potential and extensive immunomodulatory properties. In mice and rats, MSCs produce nitric oxide (NO), as immunomodulatory effector molecule that exerts an antiproliferative effect on T cells, while the role of NO in differentiation was less clear. Here, we investigated the role of NO synthase 2 (NOS2) on adipogenic and osteogenic differentiation of rat MSCs. MSCs isolated from NOS2-null (NOS2) and wild type (WT) Sprague-Dawley (SD) rats exhibited homogenous fibroblast-like morphology and characteristic phenotypes. However, after induction, adipogenic differentiation was found significantly promoted in NOS2 MSCs compared to WT MSCs, but not in osteogenic differentiation. Accordingly, qRT-PCR revealed that the adipogenesis-related genes PPAR-γ, C/EBP-α, LPL and FABP4 were markedly upregulated in NOS2 MSCs, but not for osteogenic transcription factors or marker genes. Further investigations revealed that the significant enhancement of adipogenic differentiation in NOS2 MSCs was due to overactivation of the STAT3 signaling pathway. Both AG490 and S3I-201, small molecule inhibitors that selectively inhibit STAT3 activation, reversed this adipogenic effect. Furthermore, after high-fat diet (HFD) feeding, knockout of NOS2 in rat MSCs resulted in significant obesity. In summary, NOS2 is involved in the regulation of rat MSC adipogenic differentiation the STAT3 signaling pathway.
间充质基质细胞（MSCs）是一类异质性细胞群体，具有多向分化潜能和广泛的免疫调节特性。在小鼠和大鼠中，MSCs会产生一氧化氮（NO），作为一种免疫调节效应分子，对T细胞发挥抗增殖作用，而NO在分化中的作用尚不清楚。在此，我们研究了一氧化氮合酶2（NOS2）对大鼠MSCs成脂和成骨分化的作用。从NOS2基因敲除（NOS2）和野生型（WT）Sprague-Dawley（SD）大鼠分离的MSCs表现出均一的成纤维细胞样形态和特征性表型。然而，诱导后发现，与WT MSCs相比，NOS2 MSCs的成脂分化显著促进，但成骨分化未受影响。相应地，qRT-PCR显示，NOS2 MSCs中与成脂相关的基因PPAR-γ、C/EBP-α、LPL和FABP4显著上调，但成骨转录因子或标记基因未上调。进一步研究表明，NOS2 MSCs成脂分化的显著增强是由于STAT3信号通路的过度激活。AG490和S3I-201这两种选择性抑制STAT3激活的小分子抑制剂均逆转了这种成脂作用。此外，高脂饮食（HFD）喂养后，大鼠MSCs中NOS2基因敲除导致显著肥胖。总之，NOS2通过STAT3信号通路参与大鼠MSCs成脂分化的调控。
