한빛사 논문
- 조회6,056
Mi-Ok Leea,1, Sung Hwan Moonb, Ho-Chang Jeonga, Ji-Yeon Yic, Tae-Hee Leec, Sung Han Shimb, Yong-Hee Rheed, Sang-Hun Leed, Seok-Jeong Ohe, Moo-Yeol Leee, Min-Joon Hanf, Yee Sook Chog, Hyung-Min Chungh, Kwang-Soo Kimf,2, and Hyuk-Jin Chaa,2
aDepartment of Life Sciences, College of Natural Sciences, Sogang University, Seoul 121-742, Korea;
bDepartment of Biomedical Science, College of Life Science, CHA University, Pochon-si Gyeonggi-do 487-010, Korea;
cLaboratory of Cancer and Stem Cell Biology, Plant Engineering Institute, Sejong University, Seoul 143-747, Korea;
dDepartment of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea;
eCollege of Pharmacy, Dongguk University, Seoul 100-715, Korea;
fMolecular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478;
gStem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea; and
hDepartment of Stem Cell Biology, Konkuk University School of Medicine, Seoul 143-701, Korea
1Present address: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
2To whom correspondence may be addressed.
Author contributions: M.-O.L., K.-S.K., and H.-J.C. designed research; M.-O.L., S.H.M., H.-C.J., J.-Y.Y., T.-H.L., S.H.S., Y.-H.R., S.-J.O., and M.-J.H. performed research; Y.S.C. contributed new reagents/analytic tools; M.-O.L., S.-H.L., M.-Y.L., H.-M.C., K.-S.K., and H.-J.C. analyzed data; and M.-O.L., K.-S.K., and H.-J.C. wrote the paper.
Edited* by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved July 5, 2013 (received for review February 26, 2013)
Abstract
The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
논문정보
- Research article
- 2013년 08월 (BRIC 등록일 2013-08-06)
- 국내(교신)+국외 연구진
- 의약학 > 약학
- 120회 이상 인용된 논문
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