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The Stem Cells Group

Stem cell research for the establishment of novel technologies to manipulate stem cells

　Stem cells are generally defined as cells having the ability for both Self-renewal and multi-differentiation. Tissue-specific stem cells produce the more differentiated cells that function as a part of their specific tissues and organs, and also govern the maintenance of their tissue of origin. These stem cells have been observed in many types of tissues,including bone marrow, muscle, cornea, skin and intestine.More recently, tissue-specific stem cells reportedly also been identified in nerve, myocardium, pancreas and liver tissues.

　We aim to elucidate the underlying mechanisms by which tissue-specific stem cells are commonly regulated in many type of tissues or organs through comparing hematopoietic stem cells (HSCs) and cornea limbus epithelium side-population cells (corneal epithelium stem cell) which we for the first time found and characterized. This should enable us to establish novel technology to manipulate stem cells for regenerative medicine.

　So far, we showed that high expression of integrin β3(CD61) and nectin-3 is an attribute of both rabbit corneal epithelial stem cells and mouse HSCs. Since the study of HSCs is currently one of most established fields in stem cell research, we mainly utilized HSCs to elucidate the relationship between tissue-specific stem cells and integrin β3, and found that integrin β3 plays an essential role in the maintenance of HSC activity either in vivo or in vitro. In addition,our data suggested that integrin β3 signaling contributed to enhanced expression in genes that are involved with the maintenance of HSC activity by collaborating with the cytokine signaling. Furthermore, specific ligation of β3integrin on HSCs using an agonist antibody or extra cellular matrix protein prevented loss of long-term repopulating(LTR) activity during ex vivo culture, indicating that integrinβ3 is required for cytokine-dependent maintenance of HSC activity. These are collaborative study with Professor Hiromitsu NAKAUCHI, the Institute of Medical Science, University of Tokyo, and Professor Koji ETO, the Center for iPS Cell Research and Application, Kyoto University. Currently,we are attempting to further elucidate the mechanism for the regulation of stem cells through investigating the genes of which expression was significantly affected by integrin β3 signaling.

Fig.1:
Strategies for tissue stem cell　research

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Fig.2：
Mechanism for active maintenance of stem cells by integrin β3
A：Activation of integrin αvβ3 (integrin β3) by cytokine Signal
B：Increase in stem-ness gene expression by integrin β3 signal and cytokine signal

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Researcher Introduction

Institute of Advanced BioMedical Engineering and Science,
Instructor　　Terumasa UMEMOTO

Terumasa UMEMOTO　Recently, stem cell research has been actively advanced, according to development of regenerative medicine. However, it still remains difficult challenge that tissue-specific stem cells are expanded without loss of their stem cell activity in vitro. Therefore,we aim to establish a novel technology to manipulate stem cells for regenerative medicine through the basic research to elucidate the mechanisms for the regulation of stem cells. We believe that our studies or established technologies contribute to not only regenerative medicine using tissue-specific stem cells, but also the study for the induction of target cell from iPS cells in the future.

 

Achievements

  • Kusanagi R, Umemoto T, Yamato M, Matsuzaki Y, Nishida K, Kobayashi Y, Fukai F, Okano T. Nectin-3 expression is elevated in limbal epithelial side population cells with strongly expressed stem cell markers, Biochem Biophys Res Commun. 2009;389(2):274-8.
  • Umemoto T, Yamato M, Nishida K, Yang J, Tano Y, Okano T, Limbal epithelial side population cells have stem cell-like properties, including quiescent state, Stem Cells. 2006;24(1):86 -94.
  • Umemoto T, Yamato M, Shiratsuchi Y, Terasawa M, Yang J, Nishida K, Kobayashi Y, Okano T, Expression of integrin β3 is correlated to the properties of quiescent hematopoietic stem cells possessing the side population phenotype, J Immunol. 2006;177(11):7733 -9.