Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.

Abstract

Mesenchymal stem cells (MSCs) are a source for cell-based therapy. Although MSCs have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, p-cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. After p-cresol exposure, MSC senescence was induced, as indicated by an increase in cell size and a decrease in proliferation capacity. Treatment of senescent MSCs with fucoidan significantly reversed this cellular senescence via regulation of SMP30 and p21, and increased proliferation through the regulation of cell cycle-associated proteins (CDK2, CDK4, cyclin D1, and cyclin E). These effects were dependent on FAK-Akt-TWIST signal transduction. In particular, fucoidan promoted the expression of cellular prion protein (PrPC), which resulted in the maintenance of cell expansion capacity in p-cresol-induced senescent MSCs. This protective effect of fucoidan on senescence-mediated inhibition of proliferation was dependent on the TWIST-PrPC axis. In summary, this study shows that fucoidan protects against p-cresol-induced cellular senescence in MSCs through activation of the FAK-Akt-TWIST pathway and suggests that fucoidan could be used in conjunction with functional MSC-based therapies in the treatment of CKD.

• Authors: Jun Hee Lee, Chul Won Yun, Jin Hur, Sang Hun Lee
• Journal: Marine drugs (Mar Drugs) Vol. 16 Issue 4 (Apr 06 2018) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 29642406 (Publication Type: Journal Article)

Chemical References

• Cresols
• Nuclear Proteins
• Polysaccharides
• PrPC Proteins
• TWIST1 protein, human
• Twist-Related Protein 1
• 4-cresol
• fucoidan
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cellular Senescence (drug effects)
• Cresols (toxicity)
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• Mesenchymal Stem Cell Transplantation (adverse effects)
• Mesenchymal Stem Cells (drug effects, physiology)
• Nuclear Proteins (metabolism)
• Polysaccharides (pharmacology)
• PrPC Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Renal Insufficiency, Chronic (therapy)
• Signal Transduction (drug effects)
• Twist-Related Protein 1 (metabolism)
• Up-Regulation