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

Abstract

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.

Characterization of the Secretome of a Specific Cell Expressing Mutant Methionyl-tRNA Synthetase in Co-Culture Using Click Chemistry

“…Along with this cell-based therapy, cell-free therapy using the secretome of MSCs is regarded as a promising therapeutic approach for OA [ 51 ]. Many researchers have co-cultured MSCs and chondrocyte cells in order to study the secretome of MSCs and their effect on OA [ 38 , 52 , 53 ]. They discovered that upon co-culturing with MSCs, the proliferation of chondrocyte cells increased, while the apoptosis decreased.…”

The effect of Psidium guajava hydroalcoholic extract on reducing the expression of Resistin and TNF-α genes in articular chondrocytes of patients with knee osteoarthritis

“…Some substances that are naturally present in the body may be valuable in preventing or treating osteoarthritis. Although most research is in its infancy, it is possible to use natural ingredients to heal injuries or speed up cartilage repair (18).…”

“…The high popularity of complementary and alternative drugs can be due to their advantages such as widespread availability, no side effects or low side effects, good effectiveness and low cost compared to synthetic drugs. Because osteoarthritis is an inflammatory disease associated with joint destruction, modulatory cytokines and nitric oxide produced by chondrocytes play a key role in disease progression (18).…”

Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling

“…Investigation of this in vivo observation showed that supernatants from co-culture of chondrocytes and MSCs in 3D constructs had fewer inflammatory factors than co-culture with MSCs in monolayers. An increased expression of genes related to chondrogenesis and ECM interactions were also observed, suggesting a high therapeutic potential of secretome when MSCs are cultured in 3D constructs [ 105 ]. Similarly, when MSC was encapsulated in alginate microbeads and co-cultured with patient-derived OA chondrocytes, paracrine factors induced a pro-regenerative microenvironment, increasing anabolic, proliferative, and anti-apoptotic processes [ 106 ].…”