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Glycan structures on cell surface and aging

Masashi Toyoda, Ph.D.

Theme Leader (Vascular Medicine)

The aging of the population worldwide is resulting in increasing risk of cardiovascular diseases, and creates additional burdens on medical economy. We aim at exploring the molecular mechanisms by which vascular homeostasis and cardiac regeneration are regulated during aging and disease process, focusing on the glycoconjugates (e.g., glycoproteins, glycosphingolipids (GSLs), and proteoglycans) mainly present on the cell surface. Recently we showed findings of two studies with cell and glycosphingolipids;
1) Vascular endothelial cells (ECs) play central roles in physiologically important functions of blood vessels and contribute to the maintenance of vascular homeostasis. We consider the impairment of EC functions as the development of vascular diseases, especially focusing on cell surface gangliosides that are one of GSLs. We revealed that monosialotetrahexosylganglioside (GM1) among the several gangliosides species was increased in abundance on the cell surface of ECs with cellular senescence (replicative and premature) and aging, and that the increased abundance of GM1 resulted in a state of insulin resistance in senescent ECs.

Sasaki N, Itakura Y, Toyoda M. Ganglioside GM1 contributes to the state of insulin resistance in senescent human arterial endothelial cells. J. Biol. Chem., 290:25475-25486, 2015.

2) Stem cells have the ability to divide, self-renew and to differentiate into various cell types. Stem cells have varying degrees of differentiation potential. Carbohydrate epitopes are often used as markers for definition and characterization of stem cells. Stage-specific embryonic antigens such as SSEA-3, SSEA-4, TRA-1-60 and TRA-1-81 are also used as markers for the undifferentiated state of human pluripotent stem cells, embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). We found two novel hiPSC-specific GSLs as markers for undifferentiated hiPSCs; Globo H (fucosyl-Gb5Cer) and H type1 antigen (fucosyl-Lc4Cer). We propose that the glycolipid dynamics during generation and differentiation of iPSCs will lead to a better understanding of cellular reprogramming.

Ojima T, Shibata E, Saito S, Toyoda M, Nakajima H, Yamazaki-Inoue M, Miyagawa Y, Kiyokawa N, Fujimoto J, Sato T, Umezawa A. Glycolipid dynamics in generation and differentiation of induced pluripotent stem cells. Sci. Rep., 5:14988, 2015.