Abstract
Sox9 is an intrinsic transcription factor related to the determination and maintenance of chondrogenic lineage of bone marrow mesenchymal stem cells (BMSCs). In recent research, we have proved that fragmented chondrocyte aggregates (cell bricks) could promote chondrogenesis of BMSCs in vivo. However, it is still unknown whether the ratio of BMSCs/chondrocyte bricks has a significant influence on 3-D cartilage regeneration and related molecular mechanism. To address this issue, the current study subcutaneously injected three groups of cell complex with different rabbit BMSCs/chondrocyte bricks' ratios (1 : 2, 1 : 1, and 2 : 1) into nude mice. Gross morphology observation, histological and immunohistochemical assays, biochemical analysis, gene expression analysis, and western blot were used to compare the influence of different BMSCs/chondrocyte bricks' ratios on the properties of tissue-engineered cartilage and explore the related molecular mechanism. The constructs of 1 : 1 BMSCs/chondrocyte bricks, (B1CB1) group resulted in persistent chondrogenesis with appropriate morphology and adequate central nutritional perfusion without ossification. The related mechanism is that increased expression of Sox9 in the B1C1 group promoted chondrogenesis and inhibited the osteogenesis of BMSCs through upregulating Col-II as well as downregulating RUNX2 and downstream of Col-X and Col-I by upregulating Nkx3.2. This study demonstrated that BMSCs/chondrocyte bricks 1:1 should be a suitable ratio and the Sox9-Nkx3.2-RUNX2 pathway was a related mechanism which played an important role in the niche for stable chondrogenesis of BMSCs constructed by chondrocyte bricks and PRP.
Highlights
Repair of cartilage defects has always been a great challenge in treatment due to the poor regenerative capacity of cartilage in vivo [1]
Previous studies showed that bone marrow mesenchymal stem cells (BMSCs) are easier to obtain than synovial mesenchymal stem cell (SDSC) and have a higher proliferation rate as well as higher expression of cartilage-specific genes and proteins than adipose mesenchymal stem cells (ADSCs) [8, 9], so BMSCs have been extensively investigated in cartilage regeneration [10]
We investigated the influence of the BMSC/chondrocyte bricks’ ratio and related molecular mechanism on the stable induction of BMSCs into the chondrogenic lineage
Summary
Repair of cartilage defects has always been a great challenge in treatment due to the poor regenerative capacity of cartilage in vivo [1]. Implantation with an engineered construct composed of autologous chondrocytes is currently a popular approach [2]. The lack of autologous cartilage sources and chondrocyte dedifferentiation after in vitro expansion are major obstacles to the clinical application of chondrocyte-based cartilage tissue engineering [3]. Implantation of a prothesis with a specific shape or the transplantation of autologous cartilage may cause a. Mesenchymal stem cells (MSCs) are found in numerous tissues throughout the body and are capable of self-renewal [5] and chondrogenic differentiation [6]. MSCs can be cultured and expanded in vitro, which makes them a attractive cell source for cartilage repair [7]. The engineered cartilage tissue is vascularized and ossified in vivo [14, 15]
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