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

Stem cell reports 2018 Aug 14

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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. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Kenji Kubara, Kazuto Yamazaki, Yasuharu Ishihara, Takuya Naruto, Huan-Ting Lin, Ken Nishimura, Manami Ohtaka, Mahito Nakanishi, Masashi Ito, Kappei Tsukahara, Tomohiro Morio, Masatoshi Takagi, Makoto Otsu. Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity. Stem cell reports. 2018 Aug 14;11(2):380-394