He Jing, Zhang Nihui, Zhu Yue, Jin Rongrong, Wu Fang
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
Biomaterials. 2021 Jan;265:120448. doi: 10.1016/j.biomaterials.2020.120448. Epub 2020 Oct 10.
It is critical for the clinical success to take the anti-inflammatory function into consideration when integrating the neurogenesis into the nerve repair materials. To this aim, we prepared mesenchymal stem cell (MSC) spheroids-loaded collagen (Col) hydrogels with combined superior anti-inflammatory efficacy and neurogenic activity. The size of the MSC spheroids showed a strong modulation effect on both functions, and the MSC spheroids-100 sample exhibited the best neuronal and anti-inflammatory potentials. The observed dual functions were likely based on the elevated intrinsic cell-cell contacts and cell-extracellular matrix interactions from the MSC spheroids. MSC self-assembly as spheroids expedited the secretions of endogenous trophic factors and extracellular matrix (ECM), which was beneficial to drive neural stem cell differentiation into the neuronal lineage. In addition, the formation of the MSC spheroids secreted more amounts and types of cytokines as well as immunomodulatory paracrine factors to suppress LPS-induced inflammatory reaction. LC-MS/MS analysis further demonstrated that MSC spheroids contributed to the activation of neuroactive ligand-receptor interaction, thereby triggering downstream PI3K-Akt signal pathway, which was likely due to the acceleration of ECM-receptor interaction, gap junction and tight junction. Importantly, inhibiting Akt pathway significantly suppressed the neuronal differentiation, indicating that PI3K-Akt signal pathway was critically involved in the Col-MSC spheroid hydrogel mediated neuroprotection and neurogenesis. Such findings not only provided a simple approach for improving MSC-based therapies for neuron-related diseases, but also shed insight on understanding the underlying mechanisms of MSC-mediated neuronal differentiation.
在将神经发生整合到神经修复材料中时，考虑抗炎功能对于临床成功至关重要。为此，我们制备了负载间充质干细胞（MSC）球体的胶原蛋白（Col）水凝胶，其具有卓越的抗炎功效和神经生成活性。MSC球体的大小对这两种功能均显示出强烈的调节作用，且MSC球体-100样本表现出最佳的神经元和抗炎潜力。观察到的双重功能可能基于MSC球体中细胞间接触和细胞与细胞外基质相互作用的增强。MSC自组装成球体加速了内源性营养因子和细胞外基质（ECM）的分泌，这有利于驱动神经干细胞分化为神经元谱系。此外，MSC球体的形成分泌了更多数量和种类的细胞因子以及免疫调节旁分泌因子，以抑制脂多糖诱导的炎症反应。液相色谱-串联质谱（LC-MS/MS）分析进一步表明，MSC球体有助于激活神经活性配体-受体相互作用，从而触发下游的PI3K-Akt信号通路，这可能是由于细胞外基质-受体相互作用、缝隙连接和紧密连接的加速。重要的是，抑制Akt通路显著抑制了神经元分化，表明PI3K-Akt信号通路在Col-MSC球体水凝胶介导的神经保护和神经发生中起关键作用。这些发现不仅为改善基于MSC的神经元相关疾病治疗提供了一种简单方法，也为理解MSC介导的神经元分化的潜在机制提供了见解。
