Tomé Diogo, Martins Luís F, Aroso Miguel, Santos Henrique, Costa Rui O, Afonso João L, Serra Sofia C, Aguiar Paulo, Duarte Carlos B, Peça João, Pinheiro Paulo S, Salgado António J, Almeida Ramiro D
iBiMED- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
iScience. 2025 Aug 19;28(9):113401. doi: 10.1016/j.isci.2025.113401. eCollection 2025 Sep 19.
Mesenchymal stromal cells (MSCs) have been proposed as a promising therapeutic tool for traumatic disorders of the nervous system, due to their neuro-regenerative properties. These outcomes have been extensively connected to paracrine mechanisms. Because synaptic reintegration of injured axons into existing circuitry is required for functional recovery, we investigated the synaptogenic potential of MSC secretome. Using neuronal primary cultures, hippocampal organotypic slices, and human cortical brain organoids, we found that MSC secretome induces presynaptic differentiation. Moreover, the number of axodendritic synapses also increases after treatment with MSC secretome. This increase in synapses correlates with an enhancement in synaptic activity, revealing that newly formed synapses are functional. Finally, we unraveled the mechanism underlying this effect and identified thrombospondin-1 (TSP1) as the major synaptogenic factor in MSC secretome. Together, our findings demonstrate that MSC secretome displays synaptogenic properties, pointing to a potential role as a cell-free therapy to restore lost synaptic connectivity.
间充质基质细胞（MSCs）因其神经再生特性，被认为是治疗神经系统创伤性疾病的一种有前景的治疗工具。这些结果与旁分泌机制密切相关。由于损伤轴突重新整合到现有神经回路中以实现功能恢复，我们研究了MSC分泌组的突触生成潜力。利用神经元原代培养物、海马器官型切片和人类皮质脑类器官，我们发现MSC分泌组可诱导突触前分化。此外，用MSC分泌组处理后，轴突树突突触的数量也会增加。突触数量的增加与突触活动的增强相关，表明新形成的突触具有功能。最后，我们揭示了这种效应的潜在机制，并确定血小板反应蛋白-1（TSP1）是MSC分泌组中的主要突触生成因子。总之，我们的研究结果表明，MSC分泌组具有突触生成特性，表明其作为一种无细胞疗法来恢复失去的突触连接可能发挥作用。
