UC-MSCs based on biomimetic microniche exert excellent regulatory effects on acute brain inflammation through advantageous properties

Abstract

Neuroinflammation triggered by activated microglia leads to neuronal damage and, to a certain extent, neurodegeneration. Human umbilical cord mesenchymal stem cells (UC-MSCs) have good immunomodulatory and neuroprotective effects as well as therapeutic potential for neuroinflammation-related diseases. However, the complex microenvironment created by neuroinflammation poses a challenge to transplanted UC-MSCs. The emerging biomimetic microniche (BN)-based culture technology provides new opportunities to optimize the preparation of UC-MSCs; but the fundamental changes in the characteristics of UC-MSCs based on BN remain unclear, and more reliable preclinical data are needed to support their ability to regulate inflammation. Here, we systematically studied the cellular properties and inflammation regulatory capacity of UC-MSCs in conventional static planar culture (SP-UCMSCs) and suspension culture based on BN (BN-UCMSCs). In vitro, compared with SP-UCMSCs, BN-UCMSCs not only maintained the fundamental characteristics of MSCs, but also significantly enhanced cell proliferation, adhesion, and migration capabilities, etc; notably, the paracrine function and anti-inflammatory capacity of BN-UCMSCs were also enhanced. We further established a murine model of acute brain inflammation and demonstrated that the expression level of pro-inflammatory cytokines in hippocampal and cortical tissues of the BN-UCMSCs group was significantly decreased compared with that in the SP-UCMSCs group. Subsequent transcriptomic analysis of hippocampal and cortical tissues revealed that BN-UCMSCs had the advantage of significantly reducing the expression of pro-inflammatory cytokines through the TLR4-Myd88-NF-κB axis, which was further validated at the gene and protein levels. Taken together, these data strongly indicated that BN-UCMSCs exerts excellent regulatory effects on acute brain inflammation through advantageous properties.