BACKGROUND: Matrix metalloproteinases (MMPs) are proteins involved in the repair and remodeling the extracellular matrix (ECM). MMP13 is essential for bone development and healing through the remodeling of type I collagen (COL1), the main component of the ECM in bone tissue. Mesenchymal stem cells (MSCs)-based cell therapy has been considered a promising approach for bone regeneration because of their osteogenic properties. However, the approaches using MSC to completely regenerate bone tissue have been limited. To overcome the limitation, genetic engineering of MSC could be a strategy for promoting regeneration efficacy. METHODS: We performed in vitro and in vivo experiments using MMP13-overexpressing MSCs in the presence of COL1. To examine MMP13-overexpressing MSCs in vivo, we prepared a fibrin/COL1-based hydrogel to encapsulate MSCs and subcutaneously implanted gel-encapsulated MSCs in nude mice.We found that the osteogenic marker genes, ALP and RUNX2, were upregulated in MMP13-overexpressing MSCs through p38 phosphorylation. In addition, MMP13 overexpression in MSCs stimulated the expression of integrin a3, which is upstream receptor of p38, and substantially increased osteogenic differentiation potential of MSCs. Bone tissue formation in MMP13-overexpressing MSCs was significantly higher than that in control MSCs. Taken together, our findings demonstrate that MMP13 is not only an essential factor for bone development and bone healing but also has a pivotal role in promoting osteogenic differentiation of MSCs to induce bone formation. CONCLUSION MSCs Genetically engineered to overexpress MMP13, which have a powerful potential to differentiate into the osteogenic cells, might be beneficial in bone disease therapy.

BACKGROUND: Mesenchymal stem cells (MSCs) are used for tissue regeneration due to their wide differentiation capacity and anti-inflammatory effects. Extracellular vesicles (EVs) derived from MSCs are also known for their regenerative effects as they contain nucleic acids, proteins, lipids, and cytokines similar to those of parental cells. There are several studies on the use of MSCs or EVs for tissue regeneration. However, the combinatorial effect of human MSCs (hMSCs) and EVs is not clear. In this study, we investigated the combinatorial effect of hMSCs and EVs on cartilage regeneration via co-encapsulation in a hyaluronic-acid (HA)-based hydrogel. METHODS: A methacrylic-acid-based HA hydrogel was prepared to encapsulate hMSCs and EVs in hydrogels. Through in vitro and in vivo analyses, we investigated the chondrogenic potential of the HA hydrogel-encapsulated with hMSCs and EVs. RESULTS: Co-encapsulation of hMSCs with EVs in the HA hydrogel increased the chondrogenic differentiation of hMSCs and regeneration of damaged cartilage tissue compared with that of the HA hydrogel loaded with hMSCs only. CONCLUSION Co-encapsulation of hMSCs and EVs in the HA hydrogel effectively enhances cartilage tissue regeneration due to the combinatorial therapeutic effect of hMSCs and EVs. Thus, in addition to cartilage tissue regeneration for the treatment of osteoarthritis, this approach would be a useful strategy to improve other types of tissue regeneration.