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Resveratrol Battles Inflammation and Provides a Stem Cell Boost for Periodontal Repair

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Review of “Resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates” from Experimental and Molecular Medicine by Stuart P. Atkinson

Autologous mesenchymal stem cells (MSC) derived from patients diagnosed with a range of pathologies can suffer from a loss in therapeutic potential due, in part, to the detrimental effects of the disease-associated inflammatory microenvironment. While studies have identified compounds that may protect MSCs from inflammatory insults [1], relevance to MSC-based tissue engineering remains relatively unexplored.

Researchers led by Ya-Ping Pan (China Medical University, Shenyang, Liaoning, China) and Yan Jin (Fourth Military Medical University, Xi’an, Shaanxi, China) knew that aggregates of periodontal ligament stem cells (PDLSCs), which display MSC-like characteristics, derived from patients with the inflammatory gum disease periodontitis (P-PDLSCs) suffered from a loss in osteogenic differentiation potential and, therefore, reduced periodontal defect repair [2, 3]. 

In their new Experimental and Molecular Medicine study, Wang et al. report that the natural phytoalexin resveratrol (RSV), previously established to enhance MSC-mediated liver and cardiac regeneration [4, 5], can reverse inflammation-mediated effects, promote cell aggregation, and enhance PDLSC-mediated periodontal defect repair [6].

Initial studies confirmed that in comparison to healthy PDLSCs, P-PDLSCs formed sparser and thinner cell aggregates and displayed defects in osteogenesis, including lower alkaline phosphatase (ALP) activity and weaker mineralizing capabilities. To confirm that inflammation induced these defects, the authors treated healthy PDLSCs with an inflammatory cytokine (tumor necrosis factor alpha, or TNF-α), discovering the emergence of similar defects to those observed in P-PDLSCs.

Encouragingly, the exposure of TNF-α-treated PDLSCs to RSV reversed inflammation-induced defects, as evidenced by thicker cell aggregate formation and improved osteogenic potential of cell aggregates (increased ALP activity, mineralization, and expression levels of osteogenic marker genes), potentially via the RSV-mediated restoration of NFκB signaling and the subsequent stimulation of the Sirt1-Pgc1α and AMPK signaling pathways. 

RSV treatment also enhanced the ability of TNF-α-treated PDLSCs aggregates to form bone tissue and collagen bone matrix production in the dorsal region of nude mice, suggestive of heightened regenerative potential, while RSV preconditioning of both PDLSC- and TNF-α-treated PDLSC-aggregates successfully boosted the regeneration of rat periodontal defects four weeks after transplantation.

Overall, the authors establish RSV treatment as a means to balance out the effects of the disease-associated inflammatory microenvironment and boost the application of autologous MSC-aggregate as a potentially exciting tissue engineering solution for periodontal and bone repair in healthy and diseased patients.

For more on resveratrol, stem cell aggregates, and periodontal repair stay tuned to the Stem Cells Portal.

References

  1. Sun J, Dong Z, Zhang Y, et al., Osthole improves function of periodontitis periodontal ligament stem cells via epigenetic modification in cell sheets engineering. Scientific Reports 2017;7:5254.
  2. Chen X, Hu C, Wang G, et al., Nuclear factor-κB modulates osteogenesis of periodontal ligament stem cells through competition with β-catenin signaling in inflammatory microenvironments. Cell Death &Amp; Disease 2013;4:e510.
  3. Kong X, Liu Y, Ye R, et al., GSK3β is a checkpoint for TNF-α-mediated impaired osteogenic differentiation of mesenchymal stem cells in inflammatory microenvironments. Biochimica et Biophysica Acta (BBA) - General Subjects 2013;1830:5119-5129.
  4. Pınarlı FA, Turan NN, Güçlü Pınarlı F, et al., Resveratrol and Adipose-derived Mesenchymal Stem Cells Are Effective in the Prevention and Treatment of Doxorubicin Cardiotoxicity in Rats. Pediatric Hematology and Oncology 2013;30:226-238.
  5. Okay E, Simsek T, Subasi C, et al., Cross Effects of Resveratrol and Mesenchymal Stem Cells on Liver Regeneration and Homing in Partially Hepatectomized Rats. Stem Cell Reviews and Reports 2015;11:322-331.
  6. Wang Y-J, Zhao P, Sui B-D, et al., Resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates. Experimental & Molecular Medicine 2018;50:74.