Generation and trapping of a mesoderm biased state of human pluripotency.
Generation and trapping of a mesoderm biased state of human pluripotency.
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DOI：
10.1038/s41467-020-18727-8
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发表时间：
2020-10-05
影响因子：
16.6
通讯作者：
Enver T
中科院分区：
文献类型：
--
作者：
Stavish D;Böiers C;Price C;Frith TJR;Halliwell J;Saldaña-Guerrero I;Wray J;Brown J;Carr J;James C;Barbaric I;Andrews PW;Enver T
我们假设，退出多能性涉及中间体，保留多能性，同时表现出谱系偏见。使用MIXL1报告，我们探讨中胚层谱系偏见内的人多能干细胞室。我们确定了一个substate，它在单细胞水平共表达多能和中胚层基因表达程序。在功能上，这些细胞启动干细胞培养，并在分化测定中表现出中胚层偏倚。通过操纵WNT信号传导促进中胚层身份，同时使用溶血磷脂酸防止退出多能性，我们通过多次传代将细胞“捕获”并维持在谱系偏向的干细胞状态。这些细胞对应于分化轨迹上的正常状态，其可塑性通过去除分化线索后它们重新获得无偏状态来证明。使用“交叉拮抗”信号转导来捕获具有不同谱系偏好的多能干细胞中间体可能在再生医学细胞的有效生产中具有普遍适用性。多能细胞在再生医学中的应用需要了解它们如何退出多能性。在这里，作者证明了多能性退出涉及多能性中间体的想法，通过识别和捕获中胚层偏向亚状态的文化表现出谱系偏见的支持。
We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes. Functionally these cells initiate stem cell cultures and exhibit mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we ‘trap’ and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of ‘cross-antagonistic’ signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine. Application of pluripotent cells in regenerative medicine requires an understanding of how they exit pluripotency. Here the authors demonstrate support for the idea that pluripotency exit involves pluripotent intermediates that exhibit lineage bias by identifying and trapping a mesoderm biased sub-state in culture.
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影响因子：
7.7
作者：
Frith TJ;Granata I;Wind M;Stout E;Thompson O;Neumann K;Stavish D;Heath PR;Ortmann D;Hackland JO;Anastassiadis K;Gouti M;Briscoe J;Wilson V;Johnson SL;Placzek M;Guarracino MR;Andrews PW;Tsakiridis A
通讯作者：
Tsakiridis A
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：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
4.8
作者：
Bakre, Manjiri Manohar;Hoi, Aina;Stanton, Lawrence W.
通讯作者：
Stanton, Lawrence W.
影响因子：
5.9
作者：
Allison TF;Smith AJH;Anastassiadis K;Sloane-Stanley J;Biga V;Stavish D;Hackland J;Sabri S;Langerman J;Jones M;Plath K;Coca D;Barbaric I;Gokhale P;Andrews PW
通讯作者：
Andrews PW