title: LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson's disease model.
abstract: The original properties of tissue-specific stem cells, regardless of their tissue origins, are inevitably altered during in vitro culturing, lessening the clinical and research utility of stem cell cultures. Specifically, neural stem cells derived from the ventral midbrain lose their dopamine neurogenic potential, ventral midbrain-specific phenotypes, and repair capacity during in vitro cell expansion, all of which are critical concerns in using the cultured neural stem cells in therapeutic approaches for Parkinson's disease. In this study, we observed that the culture-dependent changes of neural stem cells derived from the ventral midbrain coincided with loss of RNA-binding protein LIN28A expression. When LIN28A expression was forced and sustained during neural stem cell expansion using an inducible expression-vector system, loss of dopamine neurogenic potential and midbrain phenotypes after long-term culturing was blocked. Furthermore, dopamine neurons that differentiated from neural stem cells exhibited remarkable survival and resistance against toxic insults. The observed effects were not due to a direct action of LIN28A on the differentiated dopamine neurons, but rather its action on precursor neural stem cells as exogene expression was switched off in the differentiating/differentiated cultures. Remarkable and reproducible behavioural recovery was shown in all Parkinson's disease rats grafted with neural stem cells expanded with LIN28A expression, along with extensive engraftment of dopamine neurons expressing mature neuronal and midbrain-specific markers. These findings suggest that LIN28A expression during stem cell expansion could be used to prepare therapeutically competent donor cells.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 3 Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Kim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: A-Young
authors.initials: AY
authors.lastname: Jo
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Mi-Yoon
authors.initials: MY
authors.lastname: Chang
authors.affiliation: 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 3 Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.affiliation: 4 Department of Biomedical Science, Graduate School, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Sang-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 3 Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Jae-Jin
authors.initials: JJ
authors.lastname: Song
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 3 Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Oh
authors.affiliation: 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Yi
authors.affiliation: 5 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.affiliation: 6 Department of Life Science, College of Natural Science, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Bo-Hyun
authors.initials: BH
authors.lastname: You
authors.affiliation: 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 6 Department of Life Science, College of Natural Science, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Nam
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 2 Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea 3 Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea leesh@hanyang.ac.kr.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
keywords: LIN28A; Parkinson’s disease; cell transplantation; neural stem cell (NSC) culture; repair capacity