Institute of Neuroscience, National Research Council of Italy, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy.
School of Medicine and Surgery, University of Milano-Bicocca, Piazza dell' Ateneo Nuovo 1, 20126 Milan, Italy.
Cells. 2024 Oct 9;13(19):1665. doi: 10.3390/cells13191665.
Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition.
人骨髓间充质干细胞可调节免疫反应，是治疗影响成人和早产儿的神经炎症性脑疾病的细胞治疗的良好候选物。最近的证据表明，通过其细胞外囊泡，间充质干细胞将脑内固有免疫细胞小胶质细胞引导向促修复功能，但小胶质细胞表型转变的机制仍在研究中。我们采用体外共培养方法结合转录组分析，发现细胞外基质是人类间充质干细胞细胞外囊泡在小胶质细胞对炎性细胞因子反应中改变最显著的途径。我们通过免疫荧光分析细胞外基质成分纤连蛋白和细胞外交联酶转谷氨酰胺酶-2，证实了细胞外基质重塑。此外，对小胶质细胞标志性功能的分析表明，细胞外基质的改变增强了小胶质细胞的皱褶形成和细胞迁移。这些发现表明，细胞外基质的改变、相关的质膜重塑以及增强的小胶质细胞迁移，是间充质干细胞促进促修复性小胶质细胞转变的新机制。
