Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Leukoc Biol. 2021 Oct;110(4):711-722. doi: 10.1002/JLB.4A0720-424R. Epub 2021 Jan 13.
High mobility group (HMG)A proteins are nonhistone chromatin proteins that bind to the minor groove of DNA, interact with transcriptional machinery, and facilitate DNA-directed nuclear processes. HMGA1 has been shown to regulate genes involved with systemic inflammatory processes. We hypothesized that HMGA1 is important in the function of mesenchymal stromal cells (MSCs), which are known to modulate inflammatory responses due to sepsis. To study this process, we harvested MSCs from transgenic (Tg) mice expressing a dominant-negative (dn) form of HMGA1 in mesenchymal cells. MSCs harvested from Tg mice contained the dnHMGA1 transgene, and transgene expression did not change endogenous HMGA1 levels. Immunophenotyping of the cells, along with trilineage differentiation revealed no striking differences between Tg and wild-type (WT) MSCs. However, Tg MSCs growth was decreased compared with WT MSCs, although Tg MSCs were more resistant to oxidative stress-induced death and expressed less IL-6. Tg MSCs administered after the onset of Escherichia coli-induced sepsis maintained their ability to improve survival when given in a single dose, in contrast with WT MSCs. This survival benefit of Tg MSCs was associated with less tissue cell death, and also a reduction in tissue neutrophil infiltration and expression of neutrophil chemokines. Finally, Tg MSCs promoted bacterial clearance and enhanced neutrophil phagocytosis, in part through their increased expression of stromal cell-derived factor-1 compared with WT MSCs. Taken together, these data demonstrate that expression of dnHMGA1 in MSCs provides a functional advantage of the cells when administered during bacterial sepsis.
高迁移率族蛋白（HMG）A 蛋白是非组蛋白染色质蛋白，可与 DNA 的小沟结合，与转录机制相互作用，并促进 DNA 指导的核过程。已经表明 HMGA1 可调节与全身炎症过程相关的基因。我们假设 HMGA1 在间充质基质细胞（MSC）的功能中很重要，已知 MSC 由于败血症可调节炎症反应。为了研究这一过程，我们从表达间充质细胞中显性负（dn）形式 HMGA1 的转基因（Tg）小鼠中收获 MSC。从 Tg 小鼠中收获的 MSC 含有 dnHMGA1 转基因，并且转基因表达不会改变内源性 HMGA1 水平。细胞的免疫表型分析以及三系分化显示 Tg 和野生型（WT）MSC 之间没有明显差异。然而，与 WT MSC 相比，Tg MSC 的生长减少，尽管 Tg MSC 对氧化应激诱导的死亡更具抵抗力，并且表达的 IL-6 较少。与 WT MSC 相反，在大肠杆菌诱导的败血症发作后给予 Tg MSC 可保持单次剂量给药时改善生存的能力。Tg MSC 的这种生存益处与较少的组织细胞死亡有关，并且还减少了组织中性粒细胞浸润和中性粒细胞趋化因子的表达。最后，与 WT MSC 相比，Tg MSC 通过增加基质细胞衍生因子-1 的表达来促进细菌清除和增强中性粒细胞吞噬作用。总之，这些数据表明，在细菌败血症期间给予 MSC 中的 dnHMGA1 表达可提供细胞的功能优势。
