Stucky Elizabeth C, Erndt-Marino Joshua, Schloss Rene S, Yarmush Martin L, Shreiber David I
Department of Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, New Jersey 08854, USA.
Department of Biomedical Engineering, The College of New Jersey, 2000 Pennington Road, Ewing, New Jersey 08628, USA.
Nano Life. 2017 Jun;7(2). doi: 10.1142/s1793984417500052.
Astroglia are well known for their role in propagating secondary injury following brain trauma. Modulation of this injury cascade, including inflammation, is essential to repair and recovery. Mesenchymal stromal cells (MSCs) have been demonstrated as trophic mediators in several models of secondary CNS injury, however, there has been varied success with the use of direct implantation due to a failure to persist at the injury site. To achieve sustained therapeutic benefit, we have encapsulated MSCs in alginate microspheres and evaluated the ability of these encapsulated MSCs to attenuate neuro-inflammation. In this study, astroglial cultures were administered lipopolysaccharide (LPS) to induce inflammation and immediately co-cultured with encapsulated or monolayer human MSCs. Cultures were assayed for the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-) produced by astroglia, MSC-produced prostaglandin E, and expression of neurotrophin-associated genes. We found that encapsulated MSCs significantly reduced TNF- produced by LPS-stimulated astrocytes, more effectively than monolayer MSCs, and this enhanced benefit commences earlier than that of monolayer MSCs. Furthermore, in support of previous findings, encapsulated MSCs constitutively produced high levels of PGE, while monolayer MSCs required the presence of inflammatory stimuli to induce PGE production. The early, constitutive presence of PGE significantly reduced astrocyte-produced TNF-, while delayed administration had no effect. Finally, MSC-produced PGE was not only capable of modulating inflammation, but appears to have an additional role in stimulating astrocyte neurotrophin production. Overall, these results support the enhanced benefit of encapsulated MSC treatment, both in modulating the inflammatory response and providing neuroprotection.
星形胶质细胞在脑外伤后引发继发性损伤中所起的作用广为人知。调节包括炎症在内的这种损伤级联反应对于修复和恢复至关重要。间充质基质细胞（MSCs）在几种继发性中枢神经系统损伤模型中已被证明是营养介质，然而，由于无法在损伤部位持续存在，直接植入的使用效果不一。为了实现持续的治疗益处，我们将间充质基质细胞封装在藻酸盐微球中，并评估这些封装的间充质基质细胞减轻神经炎症的能力。在这项研究中，对星形胶质细胞培养物给予脂多糖（LPS）以诱导炎症，并立即与封装的或单层人骨髓间充质干细胞共培养。检测培养物中星形胶质细胞产生的促炎细胞因子肿瘤坏死因子α（TNF-）、骨髓间充质干细胞产生的前列腺素E以及神经营养因子相关基因的表达。我们发现，封装的间充质基质细胞显著降低了脂多糖刺激的星形胶质细胞产生的TNF-，比单层间充质基质细胞更有效，并且这种增强的益处比单层间充质基质细胞更早开始。此外，支持先前的研究结果，封装的间充质基质细胞组成性地产生高水平的PGE，而单层间充质基质细胞需要炎症刺激的存在才能诱导PGE的产生。PGE的早期、组成性存在显著降低了星形胶质细胞产生的TNF-，而延迟给药则没有效果。最后，骨髓间充质干细胞产生的PGE不仅能够调节炎症，而且似乎在刺激星形胶质细胞神经营养因子产生方面还有额外作用。总体而言，这些结果支持了封装的间充质基质细胞治疗在调节炎症反应和提供神经保护方面具有增强的益处。
