Human mesenchymal stem cells (hMSCs) secretome has been have been at the forefront of a new wave of possible therapeutic strategies for central nervous system neurodegenerative disorders, as Parkinson's disease (PD). While within its protein fraction, several promising proteins were already identified with therapeutic properties on PD, the potential of hMSCs-secretome vesicular fraction remains to be elucidated. Such highlighting is important, since hMSCs secretome-derived vesicles can act as biological nanoparticles with beneficial effects in different pathological contexts. Therefore, in this work, we have isolated hMSCs secretome vesicular fraction, and assessed their impact on neuronal survival, and differentiation on human neural progenitors' cells (hNPCs), and in a 6-hydroxydopamine (6-OHDA) rat model of PD when compared to hMSCs secretome (as a whole) and its protein derived fraction. From the results, we have found hMSCs vesicular fraction as polydispersity source of vesicles, which when applied in vitro was able to induce hNPCs differentiation at the same levels as the whole secretome, while the protein separated fraction was not able to induce such effect. In the context of PD, although distinct effects were observed, hMSCs secretome and its derived fractions displayed a positive impact on animals' motor and histological performance, thereby indicating that hMSCs secretome and its different fractions may impact different mechanisms and pathways. Overall, we concluded that the use of the secretome collected from hMSCs and its different fractions might be active modulators of different neuroregeneration mechanisms, which could open new therapeutical opportunities for their future use as a treatment for PD.

人类间充质干细胞 (hMSCs) 分泌组一直处于中枢神经系统神经退行性疾病 (如帕金森病 (PD)) 新一波可能治疗策略的前沿。虽然在其蛋白质部分中，已经确定了几种具有治疗 PD 特性的有前途的蛋白质，但 hMSCs-分泌囊泡部分的潜力仍有待阐明。这种突出显示很重要，因为 hMSCs 分泌组衍生的囊泡可以作为生物纳米颗粒，在不同的病理环境中具有有益的作用。因此，在这项工作中，我们分离了 hMSCs 分泌囊泡部分，并评估了它们对神经元存活和人类神经祖细胞 (hNPCs) 分化的影响，和 6-羟基多巴胺 (6-OHDA) 大鼠 PD 模型与 hMSCs 分泌组（作为一个整体）及其蛋白质衍生部分相比。从结果中，我们发现 hMSCs 囊泡部分作为囊泡的多分散性来源，当应用时体外能够在与整个分泌组相同的水平上诱导 hNPCs 分化，而蛋白质分离部分不能诱导这种效果。在 PD 的背景下，虽然观察到不同的影响，但 hMSCs 分泌组及其衍生组分对动物的运动和组织学表现有积极影响，从而表明 hMSCs 分泌组及其不同组分可能影响不同的机制和途径。总体而言，我们得出结论，使用从 hMSC 及其不同部分收集的分泌组可能是不同神经再生机制的活性调节剂，这可能为其未来用作 PD 治疗开辟新的治疗机会。