Abstract
BackgroundMesenchymal stem cells are a promising cell source for chondrogenic differentiation and have been widely used in several preclinical and clinical studies. However, they are prone to an unwanted differentiation process towards hypertrophy that limits their therapeutic efficacy. Matrix metallopeptidase 13 (MMP-13) is a well-known factor regulated during this undesirable event. MMP-13 is a collagen degrading enzyme, which is also highly expressed in the hypertrophic zone of the growth plate and in OA cartilage. Accordingly, we investigated the effect of MMP-13 inhibition on MSC hypertrophy.MethodsIn this study, 5-bromoindole-2-carboxylic acid (BICA) was used as an inhibitory agent for MMP-13 expression. After identifying its optimal concentration, BICA was mixed into a hydrogel and the release rate was studied. To prepare the ideal hydrogel, chondroitin sulfate (CS) and platelet lysate (PL) were mixed with sodium alginate (Alg) at concentrations selected based on synergistic mechanical and rheometric properties. Then, four hydrogels were prepared by combining alginate (1.5%w/v) and/or CS (1%w/v) and/or PL (20%v/v). The chondrogenic potential and progression to hypertrophy of human bone marrow-derived mesenchymal stem cell (hBM-MSC)-loaded hydrogels were investigated under free swelling and mechanical loading conditions, in the presence and absence of BICA.ResultsViability of hBM-MSCs seeded in the four hydrogels was similar. qRT-PCR revealed that BICA could successfully inhibit MMP-13 expression, which led to an inhibition of Coll X and induction of Coll-II, in both free swelling and loading conditions. The GAG deposition was higher in the group combining BICA and mechanical stimulation.ConclusionsIt is concluded that BICA inhibition of MMP-13 reduces MSC hypertrophy during chondrogenesis.Graphical abstract
Highlights
Articular cartilage is a highly organized tissue with poor self-healing ability caused by its avascular and aneural structure [1,2,3]
Viability of human bone marrow-derived mesenchymal stem cell (hBM-MSC) seeded in the four hydrogels was similar. qRT-polymerase chain reactions (PCR) revealed that bromoindole-2-carboxylic acid (BICA) could successfully inhibit Matrix metallopeptidase 13 (MMP-13) expression, which led to an inhibition of Coll X and induction of Coll-II, in both free swelling and loading conditions
It is concluded that BICA inhibition of MMP-13 reduces MSC hypertrophy during chondrogenesis
Summary
Articular cartilage is a highly organized tissue with poor self-healing ability caused by its avascular and aneural structure [1,2,3]. The use of an appropriate cell source is a key factor in tissue engineering. Bone marrow-derived mesenchymal stem cells (BMMSCs) have been widely used in cartilage tissue engineering due to their relative ease of isolation, proliferation capacity, and chondrogenic potential [7,8,9,10,11,12,13,14]. Mesenchymal stem cells are a promising cell source for chondrogenic differentiation and have been widely used in several preclinical and clinical studies. They are prone to an unwanted differentiation process towards hypertrophy that limits their therapeutic efficacy. We investigated the effect of MMP-13 inhibition on MSC hypertrophy
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