Chang Chia-Wen, Bale Ashwin, Bhargava Rohit, Harley Brendan A C
Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
Mater Today Bio. 2025 Jan 9;31:101475. doi: 10.1016/j.mtbio.2025.101475. eCollection 2025 Apr.
Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response to GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM conditioned media does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.
胶质母细胞瘤（GBM）是原发性脑癌中最常见且致命的类型。小胶质细胞浸润到肿瘤微环境中与免疫抑制和预后不良相关。对小胶质细胞激活和侵袭的物理化学理解的改善可能会提供新的GBM治疗策略，这对于提高长期治疗效果至关重要。在此，我们将微流控系统与三维胶原蛋白水凝胶相结合，系统地研究小胶质细胞在与GBM的相互作用中对激活、侵袭、收缩性和细胞因子分泌的反应。GBM炎症生物分子显著促进小胶质细胞的激活和三维侵袭。有趣的是，小胶质细胞的侵袭不受MMP活性抑制剂或细胞糖酵解的显著影响。相比之下，ROCK信号通路的抑制显著阻碍小胶质细胞的侵袭。红外显微镜分析表明，GBM条件培养基不会显著改变小胶质细胞的脂质含量。此外，GBM条件培养基导致胶原蛋白水凝胶收缩显著增加，这表明小胶质细胞收缩性对物理重塑局部细胞外基质（ECM）的重要性。我们还鉴定出一组可能有助于小胶质细胞趋化的可溶性蛋白，如TIMP-1和CXCL12。综上所述，这项研究表明GBM细胞的存在可通过增加细胞收缩性来增强小胶质细胞的侵袭，而与MMP活性和细胞糖酵解无关。
