A low dose cell therapy system for treating osteoarthritis: In vivo study and in vitro mechanistic investigations

• Published in: Bioactive materials 2022-01, Vol.7, p.478-490
• Main Authors: Wang, Bin, Liu, Wei, Li, Jiao Jiao, Chai, Senlin, Xing, Dan, Yu, Hongsheng, Zhang, Yuanyuan, Yan, Wenjin, Xu, Zhihong, Zhao, Bin, Du, Yanan, Jiang, Qing
• Format: Article
• Language: English
• Subjects: Mesenchymal stem cells; Microcarriers; Osteoarthritis; Tissue engineering; Transcriptome
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2021.05.029

Mesenchymal stem cells (MSCs) can be effective in alleviating the progression of osteoarthritis (OA). However, low MSC retention and survival at the injection site frequently require high doses of cells and/or repeated injections, which are not economically viable and create additional risks of complications. In this study, we produced MSC-laden microcarriers in spinner flask culture as cell delivery vehicles. These microcarriers containing a low initial dose of MSCs administered through a single injection in a rat anterior cruciate ligament (ACL) transection model of OA achieved similar reparative effects as repeated high doses of MSCs, as evaluated through imaging and histological analyses. Mechanistic investigations were conducted using a co-culture model involving human primary chondrocytes grown in monolayer, together with MSCs grown either within 3D constructs or as a monolayer. Co-culture supernatants subjected to secretome analysis showed significant decrease of inflammatory factors in the 3D group. RNA-seq of co-cultured MSCs and chondrocytes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed processes relating to early chondrogenesis and increased extracellular matrix interactions in MSCs of the 3D group, as well as phenotypic maintenance in the co-cultured chondrocytes. The cell delivery platform we investigated may be effective in reducing the cell dose and injection frequency required for therapeutic applications. •We developed MSC-laden microcarriers in spinner flask culture as cell delivery vehicles to solve those difficulties in alleviating the progression of osteoarthritis by using exogenous MSC.•We performed in vivo study and in vitro investigation to illustrate the mechanism of therapeutic effect.•We demonstrated that microniches may allow a single low dose of MSCs to achieve similar restorative effects as repeated high doses of MSCs, as indicated by radiological, μ-CT and histological analyses.•Beside, we illustrated potential molecular mechanisms of interactions between MSCs and host chondrocytes in an OA environment, and investigated the contributions of cell delivery in microniches through secretome and transcriptome analyses.•The cell delivery platform we investigated may be effective in reducing the cell dose and injection frequency required for therapeutic applications.