Mesenchymal stem cells (MSCs) are a source of cell-based therapeutics, as MSCs have tissue regeneration potential. For example, one of the characteristics of mesenchymal stem cells is that they are introduced into the patient’s body at a stage just before they become the target cells. As a result, they differentiate into the target cells in the body and treat the patient’s bad spots. For example, suppose osteoblasts or pre-adipocytes are put into the patient’s body. In that case, they differentiate into osteocytes or adipocytes in the body, which results in healing the affected area.

However, in chronic kidney disease (CKD), its therapeutic efficacy is obstructed by the uremic toxin p-cresol. To address this concern, researchers investigated the effects of Fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. According to the previous study, Fucoidan extracted from brown algae has several biological activities such as anti-tumor, anti-viral, anti-inflammation, anti-obesity, and immunomodulatory.

P-Cresol is a protein-bound uremic toxin that accumulates in the body of patients with impaired renal function. Due to its cytotoxic effects, CKD and HD (hypertensive kidney) patients are at increased risk of vascular injury, morbidity, and mortality (PMID: 12600960 DOI: 10.1373/49.3.470).

 Hence, in this blog, I would like to share the study “Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis” by Jun Hee Lee et al. 

First, they investigated the effect of Fucoidan, a polysaccharide, on cellular senescence in MSCs. To determine the impact of p-cresol on cellular senescence in MSCs, they assessed morphology, senescence, and proliferative capacity after treatment with p-cresol (50, 100, and 500 μM) for 72 h. Treatment with p-cresol significantly increased cell size. (See Fig. 1a,b)

Furthermore, a BrdU incorporation assay showed that treatment with p-cresol significantly reduced the proliferative effects of p-cresol on senescence. And proliferation-related signaling pathways in MSCs, senescence-associated proteins (SMP30 and p21), and cell cycle-associated proteins CDK2, CDK4, cyclin D1, and cyclins E) Western blotting assessed p-cresol. After treatment with cresol (500 μM), the anti-aging marker SMP30 was significantly decreased in a time-dependent manner (See Fig. 2a), and the expression of p21, a pro-senescence marker, was significantly increased. It also considerably increased accelerated aging markers. (See Fig. 2b) These results indicate that p-cresol induces MSC senescence and inhibits cell proliferation.

Further investigations were done to check if Fucoidan regulates the FAK-Akt-TWIST signaling pathway in a time-dependent manner in MSCs, activating the FAK-Akt-TWIST signaling pathway after treatment with Fucoidan. TWIST is a key pathway involved in restoring cellular senescence in endothelial progenitor cells. It was evaluated (10 μg/mL) for 0,  24, 48, 72 hours. FAK and Akt phosphorylation increased significantly in a time-dependent manner after fucoidan treatment, with maximal effects at 48 h. TWIST expression also rose dramatically in a time-dependent manner.

Similarly, Akt inhibition blocked TWIST mRNA and protein expression, indicating that fucoidan-mediated TWIST expression depends on FAK-Akt phosphorylation. Additionally, the results suggest that inhibition of Akt signaling increased the number of SA-β-gal-positive cells and altered the cellular morphology of MSCs. It indicates that fucoidan-mediated Akt signaling was associated with p-cresol, suggesting that it is involved in the protection of cresol-induced MSC senescence.

The expression of these proteins was assessed by Western blotting to investigate whether fucoidan-mediated TWIST expression regulates the activation of senescence- and proliferation-related proteins after p-cresol treatment. The result indicates that Fucoidan regulates senescence- and cell cycle-related proteins in p-cresol-induced senescent MSCs via the FAK-Akt-TWIST pathway.

This study, thus, confirms that Fucoidan protects MSCs from p-cresol-induced cellular senescence via activation of the FAK-Akt-TWIST pathway, suggesting that Fucoidan could be a functional MSC-based therapy in the treatment of CKD.

It is also expected that Fucoidan will be applied as a therapeutic agent for the treatment of CKD.