Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids.
Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids.
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DOI：
10.1242/dev.200679
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发表时间：
2022-10-15
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--
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细胞微环境与内在调节因子一起塑造干细胞的身份和分化能力。哺乳动物早期胚胎在体内暴露于缺氧环境中，并且似乎受益于体外缺氧培养。然而，缺氧如何影响干细胞转录网络和谱系选择仍然知之甚少。在这里，我们研究了急性和长期缺氧对胚胎和胚胎外干细胞的分子影响以及对分化潜力的功能影响。我们发现了一种时间和细胞类型特异性的转录反应，包括 HIF1α 介导的缺氧胚胎干细胞中的早期原条特征。使用 3D 原肠样分化模型，我们发现缺氧诱导的 T 表达在没有外源 WNT 激活的情况下能够实现对称性破坏和轴向伸长。当与外源性 WNT 激活相结合时，缺氧增强了类原肠胚的谱系代表性，肠道内胚层、脊索、神经中胚层祖细胞和体节高度富集的特征证明了这一点。我们的研究结果将微环境与干细胞功能直接联系起来，并为在胚胎发育模型中应用生理条件提供了理论依据。摘要：长期缺氧（氧张力降低）会诱导 WNT 通路活性，并可用于增强胚胎干细胞向类原肠细胞的分化。
The cellular microenvironment, together with intrinsic regulators, shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia influences stem cell transcriptional networks and lineage choices remain poorly understood. Here, we investigated the molecular effects of acute and prolonged hypoxia on embryonic and extra-embryonic stem cells as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem cells mediated by HIF1α. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. When combined with exogenous WNT activation, hypoxia enhances lineage representation in gastruloids, as demonstrated by highly enriched signatures of gut endoderm, notochord, neuromesodermal progenitors and somites. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development. Summary: Prolonged hypoxia (reduced oxygen tension) induces WNT pathway activity and is harnessed to enhance differentiation of embryonic stem cells into gastruloids.
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影响因子：
23.9
作者：
Brookes, Emily;de Santiago, Ines;Hebenstreit, Daniel;Morris, Kelly J.;Carroll, Tom;Xie, Sheila Q.;Stock, Julie K.;Heidemann, Martin;Eick, Dirk;Nozaki, Naohito;Kimura, Hiroshi;Ragoussis, Jiannis;Teichmann, Sarah A.;Pombo, Ana
通讯作者：
Pombo, Ana
SOX2水平调节负责脊椎动物体形成的祖细胞祖细胞中Wnt介质的染色质占用率。
影响因子：
21.3
作者：
通讯作者：
--
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：
Aguilera-Castrejon, Alejandro;Oldak, Bernardo;Hanna, Jacob H.
通讯作者：
Hanna, Jacob H.
影响因子：
11.4
作者：
DUBOULE, D;DOLLE, P
通讯作者：
DOLLE, P