Abstract
Adipose-derived mesenchymal stromal cells (Ad-MSCs) are a promising tool for articular cartilage repair and regeneration. However, the terminal hypertrophic differentiation of Ad-MSC-derived cartilage is a critical barrier during hyaline cartilage regeneration. In this study, we investigated the role of matrilin-3 in preventing Ad-MSC-derived chondrocyte hypertrophy in vitro and in an osteoarthritis (OA) destabilization of the medial meniscus (DMM) model. Methacrylated hyaluron (MAHA) (1%) was used to encapsulate and make scaffolds containing Ad-MSCs and matrilin-3. Subsequently, the encapsulated cells in the scaffolds were differentiated in chondrogenic medium (TGF-β, 1–14 days) and thyroid hormone hypertrophic medium (T3, 15–28 days). The presence of matrilin-3 with Ad-MSCs in the MAHA scaffold significantly increased the chondrogenic marker and decreased the hypertrophy marker mRNA and protein expression. Furthermore, matrilin-3 significantly modified the expression of TGF-β2, BMP-2, and BMP-4. Next, we prepared the OA model and transplanted Ad-MSCs primed with matrilin-3, either as a single-cell suspension or in spheroid form. Safranin-O staining and the OA score suggested that the regenerated cartilage morphology in the matrilin-3-primed Ad-MSC spheroids was similar to the positive control. Furthermore, matrilin-3-primed Ad-MSC spheroids prevented subchondral bone sclerosis in the mouse model. Here, we show that matrilin-3 plays a major role in modulating Ad-MSCs’ therapeutic effect on cartilage regeneration and hypertrophy suppression.
Highlights
Mesenchymal stem cells (MSCs) are thoroughly evaluated cell candidates for cartilage tissue engineering
We demonstrated that Adipose-derived mesenchymal stromal cells (Ad-MSCs)-derived chondrocyte hypertrophy could be suppressed by matrilin-3 in a Methacrylated hyaluron (MAHA) hydrogel system
The expression of the hypertrophic phenotype in Ad-MSC-derived chondrocytes is a concern for cartilage tissue regeneration
Summary
Mesenchymal stem cells (MSCs) are thoroughly evaluated cell candidates for cartilage tissue engineering. The expression of chondrocyte hypertrophy and ossification-associated genes, including collagen type 10, matrix metalloproteinase-13 (MMP-13), alkaline phosphatase, parathyroid hormone-related protein receptor (PTHrP-R), and vascular endothelial growth factor (VEGF), has been reported as a result of in vitro MSC chondrogenic cultures [1,2,3,4,5,6]. The expression of these genes suggests that MSC-derived chondrocytes undergo terminal hypertrophic differentiation involving apoptosis followed by ossification. The binding of matrilin-3 to BMP2 prevents BMP-receptor-mediated Smad phosphorylation and BMP2-downstream signaling, which are needed for collagen 10 expression in chondrocytes [25]
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