Abstract
Mesenchymal stem cells (MSCs) are promising cells to treat cartilage defects due to their chondrogenic differentiation potential. However, an inflammatory environment during differentiation, such as the presence of the cytokine TNFα, inhibits chondrogenesis and limits the clinical use of MSCs. On the other hand, it has been reported that exposure to TNFα during in vitro expansion can increase proliferation, migration, and the osteogenic capacity of MSCs and therefore can be beneficial for tissue regeneration. This indicates that the role of TNFα on MSCs may be dependent on the differentiation stage. To improve the chondrogenic capacity of MSCs in the presence of an inflamed environment, we aimed to determine the effect of TNFα on the chondrogenic differentiation capacity of MSCs. Here, we report that TNFα exposure during MSC expansion increased the chondrogenic differentiation capacity regardless of the presence of TNFα during chondrogenesis and that this effect of TNFα during expansion was reversed upon TNFα withdrawal. Interestingly, pre-treatment with another pro-inflammatory cytokine, IL-1β, did not increase the chondrogenic capacity of MSCs indicating that the pro-chondrogenic effect is specific for TNFα. Finally, we show that TNFα pre-treatment increased the levels of SOX11 and active β-catenin suggesting that these intracellular effectors may be useful targets to improve MSC-based cartilage repair. Overall, these results suggest that TNFα pre-treatment, by modulating SOX11 levels and WNT/β-catenin signaling, could be used as a strategy to improve MSC-based cartilage repair.
Highlights
Cartilage has a limited repair capacity and, if left untreated after damage, it will often undergo progressive, irreversible degeneration
To identify a possible TNFα target pathway in the pre-treated Mesenchymal stem cells (MSCs), we investigated the levels of the SOXC protein (SOX4 and SOX11), this group of SRY-related transcription factors was previously described to be stabilized by TNFα and involved in cartilage primordia and growth plate formation (Kato et al, 2015; Bhattaram et al, 2018)
We demonstrated that TNFα pre-treatment of MSCs in monolayers reduced the inhibitory effect of TNFα during chondrogenic differentiation by boosting the chondrogenic capacity of these cells
Summary
Cartilage has a limited repair capacity and, if left untreated after damage, it will often undergo progressive, irreversible degeneration. Mesenchymal stem cells (MSCs) are promising cells for cell-based cartilage regeneration approaches (Caplan, 1991; Caplan and Dennis, 2006) because ease of isolation, chondrogenic potential (Johnstone et al, 1998; Pittenger et al, 1999) and anti-inflammatory properties (Kinnaird et al, 2004; Caplan and Dennis, 2006; Ren et al, 2008; van Buul et al, 2012) These properties can be affected by factors present in the microenvironment, TNFα Pre-treatment Enhances MSC Chondrogenesis such as pro-inflammatory cytokines. The effect on chondrogenesis of TNFα administration during MSC expansion has been incompletely investigated whether in the presence or absence of an inflamed environment during the subsequent phase of cell differentiation
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