Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition.
Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition.
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DOI：
10.1016/j.devcel.2021.07.019
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发表时间：
2021-09-13
影响因子：
11.8
通讯作者：
Barbaric I
中科院分区：
文献类型：
--
作者：
Price CJ;Stavish D;Gokhale PJ;Stevenson BA;Sargeant S;Lacey J;Rodriguez TA;Barbaric I
人类多能干细胞（hPSCs）基因变化的出现引起了人们对其在研究和再生医学中的应用的关注。含有反复培养获得性非整倍体的变异hPSCs比野生型二倍体细胞表现出生长优势，但是产生从主要野生型向变异细胞群体漂移的机制仍然知之甚少。在这里，我们表明，通过竞争相互作用，导致野生型细胞的消除，变异克隆在马赛克培养中的优势地位得到增强。这种消除是通过快速生长的变异体的聚集和机械压缩发生的，导致f -肌动蛋白的重新分配和细胞质中yes相关蛋白（YAP）的隔离，从而诱导野生型细胞的凋亡。在野生型细胞中，YAP过表达或促进YAP核定位可减轻其“失败者”表型。我们的研究结果表明，hPSC的命运与邻近细胞施加的机械信号相耦合，并揭示劫持这一机制允许变体在培养中获得克隆优势。遗传变异的人类多能干细胞（hPSCs）消除野生型细胞机械线索介导野生型和变异的hPSCs之间的竞争性相互作用机械传感器YAP是hPSC培养中细胞竞争的关键介质细胞竞争允许变异的hPSCs快速超越培养物Price等人发现竞争性相互作用增强了遗传变异的人类多能干细胞（hPSCs）的选择优势。在快速生长的变型hPSCs存在下，野生型细胞在细胞质中隔离yes相关蛋白（YAP）并发生凋亡。邻近的变异细胞保留核YAP，保持增殖。改变培养条件会降低变异人造血干细胞的竞争优势。
The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their “loser” phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures. Genetically variant human pluripotent stem cells (hPSCs) eliminate wild-type cells Mechanical cues mediate competitive interactions of wild-type and variant hPSCs Mechanotransducer YAP is a key mediator of cell competition in hPSC cultures Cell competition allows the fast overtake of cultures by variant hPSCs Price et al. identify competitive interactions that enhance selective advantage of genetically variant human pluripotent stem cells (hPSCs). In the presence of faster-growing variant hPSCs, wild-type cells sequester yes-associated protein (YAP) in the cytoplasm and undergo apoptosis. Neighboring variant cells retain nuclear YAP, remaining proliferative. Modifying culture conditions reduces competitive advantage of variant hPSCs.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
5.9
作者：
Baker, Duncan;Hirst, Adam J.;Gokhale, Paul J.;Juarez, Miguel A.;Williams, Steve;Wheeler, Mark;Bean, Kerry;Allison, Thomas F.;Moore, Harry D.;Andrews, Peter W.;Barbaric, Ivana
通讯作者：
Barbaric, Ivana
影响因子：
3.5
作者：
Enver, T;Soneji, S;Andrews, PW
通讯作者：
Andrews, PW
影响因子：
11.8
作者：
Hashimoto, Masakazu;Sasaki, Hiroshi
通讯作者：
Sasaki, Hiroshi
影响因子：
5.9
作者：
Avery, Stuart;Hirst, Adam J.;Baker, Duncan;Lim, Chin Yan;Alagaratnam, Sharmini;Skotheim, Rolf I.;Lothe, Ragnhild A.;Pera, Martin F.;Colman, Alan;Robson, Paul;Andrews, Peter W.;Knowles, Barbara B.
通讯作者：
Knowles, Barbara B.