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Stem Cell Reports. 2018 Aug 14;11(2):380-394. doi: 10.1016/j.stemcr.2018.06.008. Epub 2018 Jul 5.

Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity.

Author information

1
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: k-kubara@hhc.eisai.co.jp.
2
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: k5-yamazaki@hhc.eisai.co.jp.
3
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
4
Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
5
Division of Stem Cell Processing/Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
6
Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
7
TOKIWA-Bio, Inc., 1-1-1 Higashi, Central 5, Tsukuba, Ibaraki 305-8565, Japan.
8
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.

Abstract

Oncogenic KRAS mutations in hematopoietic stem cells cause RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). KRAS plays essential roles in stemness maintenance in some types of stem cells. However, its roles in pluripotent stem cells (PSCs) are poorly understood. Here, we investigated the roles of KRAS on stemness in the context of induced PSCs (iPSCs). We used KRAS mutant (G13C/WT) and wild-type isogenic (WT/WT) iPSCs from the same RALD patients, as well as wild-type (WTed/WT) and heterozygous knockout (Δed/WT) iPSCs, both obtained by genome editing from the same G13C/WT clone. Compared with WT iPSCs, G13C/WT iPSCs displayed enforced retention of self-renewal and suppressed capacity for neuronal differentiation, while Δed/WT iPSCs showed normalized cellular characteristics similar to those of isogenic WTed/WT cells. The KRAS-ERK pathway, but not the KRAS-PI3K pathway, was shown to govern these G13C/WT-specific phenotypes, indicating the strong impact of the KRAS-ERK signaling upon self-renewal and differentiation propensity in human iPSCs.

KEYWORDS:

KRAS; MAPK pathway; RAS-associated autoimmune lymphoproliferative syndrome-like disease; differentiation; iPSCs; self-renewal; stemness

PMID:
29983389
PMCID:
PMC6092694
DOI:
10.1016/j.stemcr.2018.06.008
[Indexed for MEDLINE]
Free PMC Article

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