Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, 10115, Berlin, Germany.
Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology & Clinical Immunology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Drug Deliv Transl Res. 2023 Jun;13(6):1745-1765. doi: 10.1007/s13346-023-01289-9. Epub 2023 Feb 28.
There is currently no causal treatment available for Parkinson's disease (PD). However, the use of glial cell line-derived neurotrophic factor (GDNF) to provide regenerative effects for neurons is promising. Such approaches require translational delivery systems that are functional in diseased tissue. To do so, we used a non-viral Sleeping Beauty (SB) transposon system to overexpress GDNF in adipose tissue-derived mesenchymal stromal cells (adMSCs). Entrapment of cells in fibrin hydrogel was used to boost potential neurorestorative effects. Functional GDNF-adMSCs were able to secrete 1066.8 ± 169.4 ng GDNF/120,000 cells in vitro. The GDNF-adMSCs were detectable for up to 1 month after transplantation in a mild 6-hydroxydopamine (6-OHDA) hemiparkinson male rat model. Entrapment of GDNF-adMSCs enabled GDNF secretion in surrounding tissue in a more concentrated manner, also tending to prolong GDNF secretion relatively. GDNF-adMSCs entrapped in hydrogel also led to positive immunomodulatory effects via an 83% reduction of regional IL-1β levels compared to the non-entrapped GDNF-adMSC group after 1 month. Furthermore, GDNF-adMSC-treated groups showed higher recovery of tyrosine hydroxylase (TH)-expressing cells, indicating a neuroprotective function, although this was not strong enough to show significant improvement in motor performance. Our findings establish a promising GDNF treatment system in a PD model. Entrapment of GDNF-adMSCs mediated positive immunomodulatory effects. Although the durability of the hydrogel needs to be extended to unlock its full potential for motor improvements, the neuroprotective effects of GDNF were evident and safe. Further motor behavioral tests and other disease models are necessary to evaluate this treatment option adequately.
目前，帕金森病（PD）尚无因果治疗方法。然而，胶质细胞源性神经营养因子（GDNF）用于为神经元提供再生效果的方法很有前景。此类方法需要在病变组织中起作用的转译传递系统。为此，我们使用非病毒 Sleeping Beauty（SB）转座子系统在脂肪组织衍生的间充质基质细胞（adMSCs）中过表达 GDNF。细胞包埋在纤维蛋白水凝胶中可增强潜在的神经修复作用。功能性 GDNF-adMSCs 能够在体外分泌 1066.8±169.4ng GDNF/120,000 个细胞。在轻度 6-羟多巴胺（6-OHDA）半帕金森雄性大鼠模型中，移植后 GDNF-adMSCs 可检测到长达 1 个月。GDNF-adMSCs 的包埋使 GDNF 在周围组织中的分泌更加集中，也相对延长了 GDNF 的分泌时间。与非包埋 GDNF-adMSC 组相比，包埋在水凝胶中的 GDNF-adMSCs 导致局部 IL-1β 水平降低 83%，从而产生积极的免疫调节作用。1 个月后，GDNF-adMSC 治疗组中表达酪氨酸羟化酶（TH）的细胞恢复较高，表明具有神经保护功能，尽管这不足以显示运动性能的显著改善。我们的研究结果在 PD 模型中建立了一种有前途的 GDNF 治疗系统。GDNF-adMSCs 的包埋介导了积极的免疫调节作用。尽管需要延长水凝胶的耐用性以充分发挥其改善运动的潜力，但 GDNF 的神经保护作用是明显且安全的。需要进行进一步的运动行为测试和其他疾病模型以充分评估该治疗选择。
