Vascular Medicine

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

Cardiovascular disease, Stem cell, Aging and senescence, Glycan

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

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.

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.

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.

1. 1. Miyata S, Saku N, Akiyama S, Javaregowda PK, Ite K, Takashima N, Toyoda M, Yura K, Kimura T, Nishina H, Nakazawa A, Kasahara M, Nonaka H, Kiyono T, Umezawa A. Puromycin-based purification of cells with high expression of the cytochrome P450 CYP3A4 gene from a patient with drug-induced liver injury (DILI). Stem Cell Res Ther, 13(1):6, 2022. https://doi.org/10.1186/s13287-021-02680-4
2. 2. Nagai-Okatani C, Zou X, Matsuda A, Itakura Y, Toyoda M, Zhang Y, Kuno A. Tissue glycome mapping: lectin microarray-based differential glycomic analysis of formalin-fixed paraffin-embedded tissue sections. Methods Mol Biol, 2460:161-180, 2022. doi: 10.1007/978-1-0716-2148-6_10
3. 3. Ikemoto-Uezumi M, Zhou H, Kurosawa T, Yoshimoto Y, Toyoda M, Kanazawa N, Nakazawa T, Morita M, Tsuchida K, Uezumi A. Increased MFG-E8 at neuromascular junctions is an exacerbating factor for sarcopenia-associated denervation. Aging Cell, in press, 2021. https://doi.org/10.1111/acel.13536
4. 4. Sasaki N, Shinji S, Shichi Y, Ishiwata T, Arai T, Yamada T, Takahashi G, Ohta R, Sonoda H, Matsuda A, Iwai T, Takeda K, Yonaga K, Ueda K, Kuriyama S, Miyasaka T, Yoshida H. TGF-β1 increases cellular invasion of colorectal neuroendocrine carcinoma cell line through partial epithelial-mesenchymal transition. Biochem Biophys Rep. 30:101239, 2022.doi: 10.1016/j.bbrep.2022.101239
5. 5. Itakura Y, Sasaki N, Toyoda M. Glycan characteristics of human heart constituent cells maintaining organ function: relatively stable glycan profiles in cellular senescence. Biogerontology 22(6):623-637, 2021. doi: 10.1007/s10522-021-09940-z
6. 6. Sasaki N, Itakura Y, Mohsin S, Ishigami T, Kubo H, Chiba Y. Cell Surface and Functional Features of Cortical Bone Stem Cells. Int J Mol Sci 22:11849, 2021.doi: 10.3390/ijms222111849
7. 7. Tsuneishi R, Saku N, Miyata S, Akiyama S, Javaregowda PK, Ite K, Takashima N, Toyoda M, Kimura T, Kuroda M, Nakazawa A, Kasahara M, Nonaka H, Kamiya A, Kiyono T, Yamauchi J, Umezawa A. Ammonia-based enrichment and long-term propagation of zone I hepatocyte-like cells. Sci Rep 11(1):11381, 2021. doi: 10.1038/s41598-021-90708-3
8. 8. Sasaki N, Toyoda M, Ishiwata T. Gangliosides as signaling regulators in cancer. Int J Mol Sci 22(10):5076, 2021. (Review) doi: 10.3390/ijms22105076
9. 9. Minami F, Sasaki N, Shichi Y, Gomi F, Michishita M, Ohkusu-Tsukada K, Toyoda M, Takahashi K, Ishiwata T. Morphofunctional analysis of human pancreatic cancer cell lines in 2- and 3-dimensional cultures. Sci Rep, 11:7665, 2021.https://doi.org/10.1038/s41598-021-86028-1
10. 10.Gomi F, Sasaki N, Shich Y, Minami F, Shinji S, Toyoda M, Ishiwata T. Polyvinyl alcohol increased growth, migration, invasion, and sphere size in the PK-8 pancreatic ductal adenocarcinoma cell line. Heliyon, 7(2):e06182, 2021.doi: 10.1016/j.heliyon.2021.e06182
11. 11.Kurosawa T, Goto M, Kaji N, Akiyo S Mihara T, Ikemoto-Uezumi M, Toyoda M, Kanazawa N, Nakazawa T, Hori M, Uezumi A. Liver fibrosis-induced muscle atrophy is mediated by elevated levels of circulating TNFα. Cell Death Dis, 12(1):11, 2021. doi: 10.1038/s41419-020-03353-5
12. 12.Uezumi A, Ikemoto-Uezumi M, Zhou H, Kurosawa T, Yoshimoto Y, Nakatani M, Hitachi K, Yamagushi H, Watkatsuki S, Araki T, Morita M, Yamada H, Toyoda M, Kanazawa N, Nakazawa T, Hino J, Fukada S, Tsuchida K. Mesenchymally expressed Bmp3b maintains skeletal muscle integrity and reduction of its expression contributes to sarcopenia. J Ciin Investig, 131(1):e139617, 2021. doi: 10.1172/JCI139617.
13. 13.Sasaki N, Gomi F, Yoshimura H, Yamamoto M, Matsuda Y, Michishita M, Hatakeyama H, Kawano Y, Toyoda M, Korc M, Ishiwata T. FGFR4 Inhibitor BLU9931 attenuates pancreatic cancer cell proliferation and invasion while inducing senescence: evidence for senolytic therapy potential in pancreatic cancer. Cancers (Basel), 12(10):E2976, 2020. doi: 10.3390/cancers12102976.
14. 14.Nishiwaki M, Toyoda M, Oishi Y, Ishida S, Horiuchi SI, Makino-Itou H, Kimura T, Ohno SI, Ohkura T, Enosawa S, Akutsu H, Nakazawa A, Kasahara M, Kiyono T, Umezawa A. Immortalization of human hepatocytes from biliary atresia with CDK4R24C, cyclin D1, and TERT for cytochrome P450 induction testing. Sci Rep, 10(1):17503, 2020. doi: 10.1038/s41598-020-73992-3.
15. 15.Kanzaki S, Toyoda M, Umezawa A, Ogawa K. Application of mesenchymal stem cell therapy and inner ear regeneration for hearing loss: a review. Int J Mol Sci, 21(16):5764, 2020. https://doi.org/10.3390/ijms21165764
16. 16.Ikemoto Y, Miyashita T, Nasu M, Hatsune H, Kajiwara K, Fujii K, Motojima T, Kokido I, Toyoda M, Umezawa A. Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1. Aging (Albany NY), 12(10):9935-9947, 2020. doi: 10.18632/aging.103258
17. 17.Kosugi M, Otani M, Kikkawa Y, Itakura Y, Sakai K, Ito T, Toyoda M, Sekita Y, Kimura T. Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, leads to noncompaction cardiomyopathy in mice. Biochem Biophys Res Commun, 525(1):100-106, 2020. https://doi.org/10.1016/j.bbrc.2020.02.043
18. 18.Sasaki N, Itakura Y, Toyoda M. Rapamycin promotes endothelial-mesenchymal transition during stress-induced premature senescence through the activation of autophagy. Cell Commun Signal, 18(1):43, 2020. doi: 10.1186/s12964-020-00533-w
19. 19.Sasaki N, Toyoda M. Vascular diseases and gangliosides. Int J Mol Sci, 20(24), E6362, 2019.(Review) doi: 10.3390/ijms20246362
20. 20.Sasaki N, Hirabayashi K, Michishita M, Takahashi K, Hasegawa F, Gomi F, Itakura Y, Nakamura N, Toyoda M, Ishiwata T. Ganglioside GM2, highly expressed in the MIA PaCa-2 pancreatic ductal adenocarcinoma cell line, is correlated with growth, invasion, and advanced stage. Sci Rep, 9(1):19369, 2019. doi: 10.1038/s41598-019-55867-4
21. 21.Sasaki N, Gomi F, Hasegawa F, Hirano K, Fujiwara M, Toyoda M, Ishiwata T. Characterization of the metastatic potential of the floating cell component of MIA PaCa-2, a human pancreatic cancer cell line. Biochem Biophys Res Commun, 522(4):881-888, 2020. doi: 10.1016/j.bbrc.2019.11.120.
22. 22.Shichi Y, Sasaki N, Michishita M, Hasegawa F, Matsuda Y, Arai T, Gomi F, Aida J, Takubo K, Toyoda M, Yoshimura H, Takahashi K, Ishiwata T. Enhanced morphological and functional differences of pancreatic cancer with epithelial or mesenchymal characteristics in 3D culture. Sci Rep, 9(1):10871, 2019. doi: 10.1038/s41598-019-47416-w
23. 23.Sasaki N, Itakura Y, Gomi F, Hirano K, Toyoda M, Ishiwata T. Comparison of functional glycans between cancer stem cells and normal stem cells. Histol Histopathol, 34(9):995-1007, 2019. (Review). doi: 10.1007/978-981-13-8023-5_4
24. 24.Aoto S, Katagiri S, Wang Y, Pagnamenta AT, Sakamoto-Abutani R, Toyoda M, Umezawa A, Okamura K. Frequent retrotransposition of endogenous genes in ERCC2-deficient cells derived from a patient with xeroderma pigmentosum. Stem Cell Res Ther, 10(1):273, 2019. doi: 10.1186/s13287-019-1381-z.
25. 25.Sasaki N, Toyoda M, Hasegawa F, Fujiwara M, Gomi F, Ishiwata T. Fetal bovine serum enlarges the size of human pancreatic cancer spheres accompanied by an increase in the expression of cancer stem cell markers. Biochem Biophys Res Commun, 514(1):112-117, 2019. doi: 10.1016/j.bbrc.2019.04.117.
26. 26.Sasaki N, Itakura Y, Toyoda M. Gangliosides contribute to vascular insulin resistance. Int J Mol Sci, 20(8):1819, 2019. (Review) https://doi.org/10.3390/ijms20081819
27. 27.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
28. 28.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
29. 29.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
30. 30.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. https://doi.org/10.18632/aging.101540
31. 31.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
32. 32.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.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891171/
33. 33.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
34. 34.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. http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=23726
35. 35.Sasaki N, Itakura Y, Toyoda M. Sialylation regulates myofibroblast differentiation of human skin fibroblasts. Stem Cell Res Ther, 8(1):81, 2017. https://stemcellres.biomedcentral.com/articles/10.1186/s13287-017-0534-1
36. 36.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
37. 37.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
38. 38.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
39. 39.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/
40. 40.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
41. 41.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
42. 42.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. http://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-016-0079-5
43. 43.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
44. 44.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
45. 45.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
46. 46.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. http://www.jbc.org/content/290/42/25475.longhttp://biomedfrontiers.org/diabetes-obesity-2016-12/
47. 47.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
48. 48.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