Background/Purpose: Mesenchymal Stem Cells (MSCs) are stromal multipotent cells with wide regenerative and immunomodulatory properties and have been proposed as a powerful therapeutic tool. Among the mechanisms associated with their regenerative potential are their ability to differentiate into several cell lineages, as well as the production of paracrine factors, which promote the survival and proliferation of cells in damaged tissues. On the other hand, their ability to regulate the immune response, allows them to inhibit the inflammation associated with tissue damage, promoting efficient and coordinated tissue regeneration. More recently, it has been described that some biological functions of MSCs, such as their differentiation potential are regulated by their metabolic activity, suggesting that changes in their metabolic state could also be regulating their therapeutic potential. For example, for chondrogenesis, cells need maintain a glycolytic-dependent metabolism during their differentiation process². Therefore, the hypothesis of the present study is that the induction of a glycolytic state on MSCs will promote their chondrogenic differentiation, as well as their chondroprotective and immunosuppressive properties.

²Pattappa, G., Heywood, H.K, de Bruijn, J. D., & Lee, D. A. (2011) The metabolism of human mesenchymal stem cells during proliferation and differentiation. Journal of Cellular Physiology, 226(10), 2562-2570. https://doi.org/10.1002/jcp.22605

Methods:

MSCs were pretreated with either an inhibitor of glycolysis or mitochondrial metabolism during 24 hours. After that, cells were cultured in presence of a chondrogenic differentiation media. Chondrogenesis was evaluated by staining with safranin O and qRT-PCR for the chondrogenic genes aggrecan and collagen II. Separately, pretreated MSCs were co-cultured with chondrocytes (HC-a) and HC-a proliferation was measured with WST1 kit assay. Statistical analysis was performed with the Kruskal-Wallis test for the comparison of medians and Mann-Whitney as a post-hoc test.

Results:

MSCs pretreated with an inhibitor of mitochondrial metabolism (glycolytic-MSCs), have a higher level of expression of chondrogenic genes after 11 days of differentiation compared to control MSCs. Moreover, MSCs pretreated with a glycolysis inhibitor (OXPHOS-MSCs) significantly reduced their chondrogenic potential. Interestingly, it was observed that glycolytic-MSCs were able to differentiate into chondrocytes without the need of differentiation medium. Additionally, glycolytic-MSCs significantly increase the proliferation of HC-a when they are incubated in co-culture without cell contact.

Conclusion:

The inhibition of mitochondrial metabolism was able to induce chondrogenesis without the needed of a specific differentiation media. Our results suggest that the potentiation of a glycolytic state on MSCs to favor the proliferation of chondrocytes is associated to a mechanism dependent of soluble factors. These results present a new method to increase the therapeutic effect of MSCs in osteoarthritis, where the etiology of the disease is associated with inflammation and tissue destruction of the joint.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/study-of-the-metabolic-effect-of-mscs-on-their-chondroprotective-and-regenerative-properties-modulating-their-metabolism-to-improve-their-therapeutic-potential-for-the-treatment-of-osteoarthritis/