Mol. Cells 2018; 41(2): 110~118  https://doi.org/10.14348/molcells.2018.2210
Generation of Isthmic Organizer-Like Cells from Human Embryonic Stem Cells
Junwon Lee1,2,3,5, Sang-Hwi Choi1,3,5, Dongjin R Lee1,3, Dae-Sung Kim4,*, Dong-Wook Kim1,3,*
1Department of Physiology, 2Department of Ophthalmology, 3Brain Korea 21 PLUS Project for Medical Science, Yonsei University
College of Medicine, Seoul 03722, Korea, 4Department of Biotechnology, Brain Korea 21 PLUS Project for Biotechnology,
College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea, 5These authors contributed equally to this
work.
*Correspondence: dwkim2@yuhs.ac (DWK); sonnet10@korea.ac.kr (DSK)
Received September 6, 2017; Revised November 16, 2017; Accepted November 17, 2017.; Published online January 31, 2018.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-sa/3.0/).
ABSTRACT
The objective of this study was to induce the production of isthmic organizer (IsO)-like cells capable of secreting fibroblast growth factor (FGF) 8 and WNT1 from human embryonic stem cells (ESCs). The precise modulation of canonical Wnt signaling was achieved in the presence of the small molecule CHIR99021 (0.6 μM) during the neural induction of human ESCs, resulting in the differentiation of these cells into IsO-like cells having a midbrain-hindbrain border (MHB) fate in a manner that recapitulated their developmental course in vivo. Resultant cells showed upregulated expression levels of FGF8 and WNT1. The addition of exogenous FGF8 further increased WNT1 expression by 2.6 fold. Gene ontology following microarray analysis confirmed that IsO-like cells enriched the expression of MHB-related genes by 40 fold compared to control cells. Lysates and conditioned media of IsO-like cells contained functional FGF8 and WNT1 proteins that could induce MHB-related genes in differentiating ESCs. The method for generating functional IsO-like cells described in this study could be used to study human central nervous system development and congenital malformations of the midbrain and hindbrain.
Keywords: FGF, human pluripotent stem cells, isthmic organizer, neural differentiation, Wnt


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