Inhibition of pluripotent stem cell-derived teratoma formation by small molecules

Mi Ok Lee, Sung Hwan Moon, Ho Chang Jeong, Ji Yeon Yi, Tae Hee Lee, Sung Han Shim, Yong Hee Rhee, Sang Hun Lee, Seok Jeong Oh, Moo Yeol Lee, Min Joon Han, Yee Sook Cho, Hyung Min Chung, Kwang Soo Kim, Hyuk Jin Cha

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

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.

Original languageEnglish
Pages (from-to)E3281-E3290
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number35
DOIs
StatePublished - 27 Aug 2013

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