Original Article
Subject Category: Cell Therapy
Molecular Therapy (2009) 17 10, 1761–1770. doi:10.1038/mt.2009.148
Conditions for Tumor-free and Dopamine Neuron–enriched Grafts After Transplanting Human ES Cell–derived Neural Precursor Cells
Ji-Yun Ko1,2, Hyun-Seob Lee1,2, Chang-Hwan Park2,3, Hyun-Chul Koh2,4, Yong-Sung Lee1,2 and Sang-Hun Lee1,2
- 1Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea
- 2Medical Research Center, Hanyang University, Seoul, Korea
- 3Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea
- 4Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Korea
Correspondence: Sang-Hun Lee, Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, #17 Haengdang-dong, Sungdong-gu, Seoul, 133-791, Korea. E-mail: leesh@hanyang.ac.kr
Received 24 January 2009; Accepted 11 June 2009; Published online 14 July 2009.
Abstract
We have previously demonstrated derivation of neural precursor (NP) cells of a midbrain-type from human embryonic stem (hES) cells to yield an enriched population of dopamine (DA) neurons. These hES-derived NPs can be expanded in vitro through multiple passages without altering their DA neurogenic potential. Here, we studied two aspects of these hES-NP cells that are critical issues in cell therapeutic approaches for Parkinson's disease (PD): cell survival and tumorigenic potential. Neuroepithelial rosettes, a potentially tumorigenic structure, disappeared during hES-NP cell expansion in vitro. Although a minor population of cells positive for Oct3/4, a marker specific for undifferentiated hES cells, persisted in culture during hES-NP cell expansion, they could be completely eliminated by subculturing hES-NPs under differentiation-inducing conditions. Consistently, no tumors/teratomas are formed in rats grafted with multipassaged hES-NPs. However, extensively expanded hES-NP cells easily underwent cell death during differentiation in vitro and after transplantation in vivo. Transgenic expression of Bcl-XL and sonic hedgehog (SHH) completely overcame the cell survival problems without increasing tumor formation. These findings indicate that hES-NP cell expansion in conjunction with Bcl-XL+SHH transgene expression may provide a renewable and safe source of DA neurons for transplantation in PD.
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