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Vascular Medicine

Members

Theme Leader :
Masashi Toyoda, Ph.D.
Researcher :
Norihiko Sasaki, Ph.D., Yoko Itakura, Ph.D., Kensuke Ohse, Ph.D.

Keywords

Cardiovascular disease, Stem cell, Aging and senescence, Glycan

Major Research Titles

  1. 1.Vascular aging and diseases
  2. 2.Cardiac regeneration and aging
  3. 3.Stem cell biology for regenerative medicine
  4. 4.Development of the quality control method for regenerative medicine

Profile

The dramatic expansion of the size of the elderly population increases risk of cardiovascular diseases, and creates additional burdens on medical economy. Therefore, the research on the effects of aging on cardiovascular diseases is a relevant topic. We aim at exploring the molecular mechanisms by which vascular homeostasis and cardiac regeneration are regulated during aging and disease process.

1. Vascular aging and diseases
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 and try to elucidate the molecular mechanisms, focusing on the glycoconjugates (e.g., glycoproteins, glycosphingolipids, and proteoglycans) mainly present on the cell surface.
In recent years, the involvement of senescent cell-derived factors in the onset and progression of cardiovascular disease has been pointed out, and importance of cell-cell interactions in the cardiovascular system is noted. However, it has not been clarified that what kinds of senescent EC-derived factor are working. We try to elucidate the intercellular network mechanisms of the cardiovascular system focusing on glycan-related secretory factors derived from senescent ECs.

Figure 1

2. Cardiac regeneration and aging
Understanding of cellular communications (e.g., cell-cell interaction, and cellular network) for cardiac regeneration contributes to developing new tissue remodeling strategy. To regenerate the damaged heart during aging and/or disease process, we aim at searching an alternative that enables us to increase the number of cardiomyocytes and to recover the heart functions. To this aim, we have tried to understand how cardiovascular system is regulated to induce the proliferation and regulation of cardiomyocytes, fibroblasts and endothelial cells, including their characteristic. Moreover, we have focused on cardiac stem cells, and have tried to clarify the role of the cells and realize the heart remodeling.

Figure 2

3. Stem cell biology for regenerative medicine
Stem cells have a capability to self-renew and differentiate into multiple types of cells and have varying degrees of differentiation potential: pluripotency, ES cells and iPS cells; multipotentiality somatic stem cells; and unipotentiality or precursor cells. Stem cell-based therapy has become a promising strategy for the treatment of many diseases. We are mainly focusing on stem cell biology and translational research for cardiovascular disease, which is one of the disease that will continue to grow in the future in the development of the aging society. In particular, we are promoting the validation to define and monitor the status of stem cells in vitro and in vivo using glycan profiling.

4. Development of the quality control method for regenerative medicine
Novel quality control method and criteria are essential for industrialization of regenerative medicine products. This is because regenerative medicine products contain live cells and exert the therapeutic effect through multiple mode of action. We are developing the appropriate evaluation method of regenerative medicine products which are different from conventional medicine.

References

  1. 1. Sasaki N*, Itakura Y, Toyoda M*. Gangliosides contribute to vascular insulin resistance. Int. J. Mol. Sci. 20(8):1819, 2019. (Review) (*corresponding author) https://doi.org/10.3390/ijms20081819
  2. 2. Sasaki N, Toyoda M, Yoshimura H, Matsuda Y, Arai T, Takubo K, Aida J, Ishiwata T. H19 long non-coding RNA contributes to sphere formation and invasion through regulation of CD24 and integrin expression in pancreatic cancer cells. Oncotarget, 9(78):34719-34734, 2018. https://doi.org/10.18632/oncotarget.26176
  3. 3. Iso Y, Usui S, Toyoda M, Spees JL, Umezawa A, Suzuki H. Bone marrow-derived mesenchymal stem cells inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia after arterial injury in rats. Biochem Biophys Rep.,16:79-87, 2018. https://doi.org/10.1016/j.bbrep.2018.10.001
  4. 4. Nishino K, Arai Y, Takasawa K, Toyoda M, Yamazaki-Inoue M, Sugawara T, Akutsu H, Nishimura K, Ohtaka M, Nakanishi M, Umezawa A. Epigenetic-scale comparison of human iPSCs generated by retrovirus, Sendai virus or episomal vectors. Regenerative Therapy, 9:71-78, 2018. https://doi.org/10.1016/j.reth.2018.08.002
  5. 5. Itakura Y, Sasaki N, Toyoda M*. Qualitative and quantitative alterations in intracellular and membrane glycoproteins maintain the balance between cellular senescence and human aging. Aging (Albany NY), 10(8):2190-2208, 2018. (*corresponding author) https://doi.org/10.18632/aging.101540
  6. 6. Miura Y, Hashii N, Ohta Y, Itakura Y, Tsumoto H, Suzuki J, Takakura D, Abe Y, Arai Y, Toyoda M, Kawasaki N, Hirose N, Endo T. Characteristic glycopeptides associated with extreme human longevity identified through plasma glycoproteomics. Biochim. Biophys. Acta., 1862(6):1462-1471, 2018. https://www.sciencedirect.com/science/article/pii/S0304416518300874?via%3Dihub
  7. 7. Sasaki N, Ishiwata T*, Hasegawa F, Michishita M, Kawai H, Matsuda Y, Arai T, Ishikawa N, Aida J, Takubo K, Toyoda M*. Stemness and anti-cancer drug resistance in ABCG2 highly expressed pancreatic cancer is induced on 3D-culture condition. Cancer Sci., 109(4):1135-1146, 2018. (*corresponding author) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891171/
  8. 8. Takasawa K, Arai Y, Yamazaki-Inoue M, Toyoda M, Akutsu H, Umezawa A, Nishino K. DNA hypermethylation enhanced telomerase reverse transcriptase expression in human induced stem cells. Human Cell, 31(1):78-86, 2018. https://link.springer.com/article/10.1007%2Fs13577-017-0190-x
  9. 9. Sasaki N, Itakura Y, Toyoda M*. Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα. Oncotarget, 9(5):5562-5577, 2018. (*corresponding author) http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=23726
  10. 10. Sasaki N, Itakura Y, Toyoda M*. Sialylation regulates myofibroblast differentiation of human skin fibroblasts. Stem Cell Res. Ther., 8(1):81, 2017. (*corresponding author) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395757/
  11. 11. Zou X, Yoshida M, Nagai-Okatani C, Iwaki J, Matsuda A, Tan B, Hagiwara K, Sato T, Itakura Y, Noro E, Kaji H, Toyoda M, Zhang Y, Narimatsu H, Kuno A. A standardized method for lectin microarray-based tissue glycome mapping. Sci. Rep., 7:43560, 2017. https://www.nature.com/articles/srep43560
  12. 12. Seko Y, Azuma N, Yokoi T, Kami D, Ishii R, Nishina S, Toyoda M, Shimokawa H, Umezawa A. Anteroposterior patterning of gene expression in the human infant sclera:chondrogenic potential and wnt signaling. Cur. Eye Res., 42(1):145-154, 2017. http://www.tandfonline.com/doi/full/10.3109/02713683.2016.1143015
  13. 13. Tateno H, Saito S, Hiemori K, Kiyoi K, Hasehira K, Toyoda M, Onuma Y, Ito Y, Akutsu H, Hirabayashi J. α2-6sialylation is a marker of the differentiation potential of human mesenchymal stem cells. Glycobiology, 26(12):1328-1337, 2016. https://academic.oup.com/glycob/article-lookup/doi/10.1093/glycob/cww039
  14. 14. Tone H, Yoshioka S, Akiyama H, Nishimura A, Ichimura M, Nakatani M, Kiyono T, Toyoda M, Watanabe M, Umezawa A. Embryoid body-explant outgrowth cultivation from induced-plulipotent stem cells (iPSCs) in an automated closed platform. BioMed Res. Int., 2016:7098987, 2016. https://www.hindawi.com/journals/bmri/2016/7098987/
  15. 15. Okamura K, Sakaguchi H, Sakamoto-Abutani R, Nakanishi M, Nishimura K, Yamazaki-Inoue M, Ohtaka M, Periasamy VS, Alshatwi AA, Higuchi A, Hanamoka K, Nakabayashi K, Takada S, Hata K, Toyoda M, Umezawa A. Distinctive features of single nucleotide alterations in induced pluripotent stem cells with different types of DNA repair deficiency disorders. Sci. Rep., 6:26342, 2016. http://www.nature.com/articles/srep26342
  16. 16. Komuta Y, Ishii T, Kaneda M, Ueda Y, Miyamoto K, Toyoda M, Umezawa A, Seko Y. In vitro transdifferentiation of human peripheral blood mononuclear cells to photoreceptor-like cells. Biol. Open,5(6):709-719, 2016. http://bio.biologists.org/content/5/6/709.long
  17. 17. Itakura Y, Sasaki N, Kami D, Gojo S, Umezawa A, Toyoda M*. N- and O-glycan cell surface protein modifications associated with cellular senescence and human aging. Cell Biosci., 6:14, 2016. (*corresponding author) http://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-016-0079-5
  18. 18. Kitajima K, Nakajima M, Kanokoda M, kyba M, Dandaoat A, Tolar J, Saito MK, Toyoda M, Umezawa A, Hara T. GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells. Exp. Hematol., 44(1):68-74, e1-10, 2016. http://www.sciencedirect.com/science/article/pii/S0301472X15006748
  19. 19. Okamura K, Toyoda M, Hata K, Nakabayashi K, Umezawa A. Whole-exome sequencing of fibroblast and its iPS cell lines derived from a patient diagnosed with xeroderma pigmentosum. Genom. Data, 6:4-6, 2015. http://www.sciencedirect.com/science/article/pii/S221359601500152X
  20. 20. 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. http://www.nature.com/articles/srep14988
  21. 21. 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. (*corresponding author) http://www.jbc.org/content/290/42/25475.long http://biomedfrontiers.org/diabetes-obesity-2016-12/
  22. 22. Kawasaki T, Kirita Y, Kami D, Kitani T, Ozaki C, Itakura Y, Toyoda M, Gojo S. Novel detergent for whole organ tissue engineering. J. Biomed. Mater. Res. A.,103(10):3364-3373, 2015. http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.35474/abstract
  23. 23. Watada Y, Yamashita D, Toyoda M, Tsuchiya K, Hida N, Tanimoto A, Ogawa K, Kanzaki S, Umezawa A. Magnetic response monitoring of superparamagnetic iron oxide (SPIO)-labeled stem cells transplanted into the inner ear. Neurosci. Res.95;21-26, 2015. http://www.sciencedirect.com/science/article/pii/S0168010215000280
  24. 24. Lu S, Kanekura K, Hara T, Mahadevan J, Spears LD, Oslowski CM, Martinez R, Yamazaki-Inoue M, Toyoda M, Neilson A, Blanner P, Brown CM, Semenkovich CF, Marxhall BA, Hershey T, Umezawa A, Greer PA, Urano F. A calcium-dependent protease as a potential thereapeutic target for wolfram syndrome. PNAS, 111(49):E5292-52301, 2014. http://www.pnas.org/content/111/49/E5292.long
  25. 25. Terai M, Izumiyama-Shimomura N, Aida J, Ishikawa N, Kuroiwa M, Arai T, Toyoda M, Nakamura KI, Takubo K. Arm-specific telomere dynamics of each individual chromosome in induced pluripotent stem cells revealed by quantitative fluorescence in situ hybridization. Tissue cell, 46(6): 470-476, 2014. http://www.sciencedirect.com/science/article/pii/S0040816614000743?via%3Dihub