Human Cartilage-Derived Progenitors Resist Terminal Differentiation and Require CXCR4 Activation to Successfully Bridge Meniscus Tissue Tears

Abstract

Meniscus injuries are among the most common orthopaedic injuries. Tears in the inner one-third of the meniscus heal poorly and present a significant clinical challenge. In this study, we hypothesized that progenitor cells from healthy human articular cartilage (C-PCs) may be more suitable than bone-marrow mesenchymal stem cells (BM-MSCs) to mediate bridging and reintegration of fibrocartilage tissue tears in meniscus. C-PCs were isolated from healthy human articular cartilage based on their expression of mesenchymal stem/progenitor marker ALCAM (CD166). Our findings revealed that healthy human C-PCs are CD166+, CD90+, CD54+, CD106- cells with multi-lineage differentiation potential and elevated basal expression of chondrogenesis marker SOX-9. We show that, similar to BM-MSCs, C-PCs are responsive to the chemokine stromal cell derived factor-1 (SDF-1) and they can successfully migrate to the area of meniscal tissue damage promoting collagen bridging across inner meniscal tears. In contrast to BM-MSCs, C-PCs maintaining reduced expression of cellular hypertrophy marker collagen X in monolayer culture and in an ex-plant organ culture model of meniscus repair. Treatment of C-PCs with SDF-1/CXCR4 pathway inhibitor AMD3100 disrupted cell localization to area of injury and prevented meniscus tissue bridging thereby indicating that the SDF-1/CXCR4 axis is an important mediator of this repair process. This study suggests that C-PCs from healthy human cartilage may potentially be a useful tool for fibrocartilage tissue repair/regeneration because they resist cellular hypertrophy and mobilize in response to chemokine signaling.

Progenitor Cells Activated by Platelet Lysate in Human Articular Cartilage as a Tool for Future Cartilage Engineering and Reparative Strategies

“…A recent study has confirmed that chondro-progenitors are more suitable candidates for therapeutic treatment of meniscus injury than BM-MSCs since they resisted to hypertrophic differentiation during tissue repair [86]. Similarly, and according with our findings, we can suggest that PL-induced activation of such CPC population able to counteract cell hypertrophy within articular cartilage could be considered beneficial in therapeutic treatments for OA.…”

Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells

“…It has been previously surmised that the C-PC is an ideal cell type for cartilaginous tissue repair/regeneration based on: (1) their natural placement within articular cartilage tissue [ 17 ], (2) their functional phenotype (i.e., chondrogenic capacity, resistance to terminal differentiation) [ 16 , 18 ]. It is demonstrated that C-PCs exhibit low basal expression of cell hypertrophy markers during in vitro cell culture [ 16 ] and ex vivo tissue coculture, in comparison to BM-MSCs [ 18 ]. Despite differences in their functional phenotype, C-PCs and BM-MSCs share similar immunophenotypic cell surface marker profiles ( Figure 1 ).…”

“…Despite differences in their functional phenotype, C-PCs and BM-MSCs share similar immunophenotypic cell surface marker profiles ( Figure 1 ). Veritably, C-PCs satisfy the criteria outlined by the International Society for Cellular Therapy for characterizing mesenchymal stromal/stem cells [ 18 , 19 ]. Like BM-MSCs, C-PCs do not exhibit common hematopoietic stem cell surface markers CD34 and CD45; nor do they exhibit mononuclear peripheral blood-derived cell surface markers CD14 and CD11b ( Figure 1 A–C).…”

Expression and function of cartilage-derived pluripotent cells in joint development and repair

“…In culture of man-made injured meniscus explants in vitro, meniscus-derived pluripotent cells could bridge and reintegrate torn meniscal fibrocartilage along the tear channel, as evidenced by the migratory ability in response to the chemokine signaling stromal-derived factor-1/stromal-derived factor-1 receptor (SDF-1/ CXCR4) axis, a pronounced tendency toward chondrogenic differentiation, a greater than 100% increase in fibrochondrocyte proliferation, the elevated expression of Sox9 and decreased expression of type X collagen, and the resistance to cellular hypertrophy and terminal differentiation during the tissue repair process in a rat [47] and a rabbit [19] model. On this basis, Jayasuriya et al [47] proposed that the initiation of the observed meniscal tissue repair is possible without first forming a blood clot, provided that an influx of stem cells is readily available near the damage site. Furthermore, the intraarticular injection of meniscus-derived pluripotent cells can enhance the regeneration of the injured meniscus at an early stage of OA, promoting neotissue formation with an improved shape and increased mature ECM and resulting in reduced expression of OA markers such as type I collagen, type X collagen, and hypoxia-inducible factor 2a (HIF-2a) but increased expression of collagen II [17,18].…”