帕金森病 (PD) 是最常见的运动障碍，其特征是黑质纹状体系统多巴胺能神经元逐渐丧失。目前，在临床诊断之前没有任何治疗方法可以延缓疾病进展或逆转损害。间充质干细胞 (MSC) 是再生医学应用中研究最广泛的细胞来源之一，特别是由于可溶性因子和囊泡（称为分泌组）的释放。这项工作的主要目标是利用不同的疾病模型，探讨从骨髓来源的间充质干细胞 (BM-MSC) 收集的分泌蛋白组的治疗潜力。首先，我们利用优化的人类中脑特异性类器官系统，通过 6-羟基多巴胺 (6-OHDA) 暴露，使用神经毒素诱导的模型来体外模拟 PD。在体内，我们评估了 BM-MSC 分泌蛋白组的效果，比较了两种不同的分泌蛋白组给药途径：脑内注射（两个部位单次给药）与多次全身给药。 BM-MSC 的分泌组能够防止多巴胺能神经元损失，这些作用在体内更加明显。 BM-MSC分泌组导致运动功能恢复和多巴胺能丧失保护；然而，多次全身给药会产生更大的治疗效果，使得该结果与未来潜在的临床应用极为相关。

Parkinson's disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications.