Synthetic Molecules that Protect Cells from Anoikis and Their Use in Cell Transplantation†
Heidie L. Frisco-Cabanos
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Graduate School of Medicine Kyoto University (Japan)
Search for more papers by this authorDr. Mizuki Watanabe
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorDr. Naoki Okumura
Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorDr. Kosuke Kusamori
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorNaohiro Takemoto
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorJunichiro Takaya
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Graduate School of Medicine Kyoto University (Japan)
Search for more papers by this authorDr. Shin-ichi Sato
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorDr. Sayumi Yamazoe
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorProf. Yoshinobu Takakura
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Search for more papers by this authorProf. Shigeru Kinoshita
Department of Ophthalmology, Kyoto Prefectural University of Medicine (Japan)
Search for more papers by this authorCorresponding Author
Dr. Makiya Nishikawa
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Noriko Koizumi
Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Motonari Uesugi
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorHeidie L. Frisco-Cabanos
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Graduate School of Medicine Kyoto University (Japan)
Search for more papers by this authorDr. Mizuki Watanabe
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorDr. Naoki Okumura
Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorDr. Kosuke Kusamori
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
These authors contributed equally to the work.
Search for more papers by this authorNaohiro Takemoto
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorJunichiro Takaya
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Graduate School of Medicine Kyoto University (Japan)
Search for more papers by this authorDr. Shin-ichi Sato
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorDr. Sayumi Yamazoe
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorProf. Yoshinobu Takakura
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Search for more papers by this authorProf. Shigeru Kinoshita
Department of Ophthalmology, Kyoto Prefectural University of Medicine (Japan)
Search for more papers by this authorCorresponding Author
Dr. Makiya Nishikawa
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Noriko Koizumi
Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Motonari Uesugi
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Makiya Nishikawa, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501 (Japan)
Noriko Koizumi, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394 (Japan)
Motonari Uesugi, Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 (Japan)
Search for more papers by this authorWe thank Nagase & Co., Ltd. for sharing chemical samples. This work was supported in part by JSPS (LR018 to M.U. and LS117 to N.K.) and the Collaborative Research Program of the Institute for Chemical Research, Kyoto University (2013-51, 2012-10, 2011-26, and 2010-24). The Uesugi research group participates in the Global COE program “Integrated Materials Science” (no B-09). iCeMS is supported by World Premier International Research Center Initiative (WPI), MEXT (Japan). This work was inspired by the international and interdisciplinary environments of the iCeMS and JSPS Asian CORE Program, “Asian Chemical Biology Initiative”. The upgrade of the confocal microscope was supported by the New Energy and Industrial Technology Development Organization (NEDO) of Japan and Yokogawa Electric Corporation.
Abstract
One of the major problems encountered in cell transplantation is the low level of survival of transplanted cells due to detachment-induced apoptosis, called anoikis. The present study reports on the chemical synthesis and biological evaluation of water-soluble molecules that protect suspended cells from anoikis. The synthetic molecules bind to and induce clusters of integrins and heparan-sulfate-bound syndecans, two classes of receptors that are important for extracellular matrix-mediated cell survival. Molecular biological analysis indicates that such molecules prolong the survival of suspended NIH3T3 cells, at least in part, by promoting clustering of syndecan-4 and integrin β1 on the cell surface, leading to the activation of small GTPase Rac-1 and Akt. In vivo experiments using animal disease models demonstrated the ability of the molecules to improve cell engraftment. The cluster-inducing molecules may provide a starting point for the design of new synthetic tools for cell-based therapy.
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