Stem cell conversion to the cardiac lineage requires nucleotide signalling from apoptosing cells.
Stem cell conversion to the cardiac lineage requires nucleotide signalling from apoptosing cells.
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DOI：
10.1038/s41556-022-00888-x
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发表时间：
2022-04
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
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多能干细胞可以通过操纵Wnt信号传导来驱动，通过一系列类似于早期胚胎发育过程中发生的状态，从上皮表型转变为心源性中胚层谱系，并最终转变为功能性心肌细胞。引人注目的是，我们观察到诱导多能干细胞（iPSC）和胚胎干细胞（ESC）分化的启动会引发广泛的细胞凋亡，随后发生同步上皮-间质转化（EMT）。细胞凋亡是由于分化培养基中缺乏 bFGF 引起的。 EMT 需要诱导 MESP1 表达下游的转录因子 SNAI1/SNAI2，而 SNAI1/2 的双敲除或 iPSC 中 MESP1 的缺失会阻碍 EMT 并阻止心脏分化。值得注意的是，用化学方法或通过消除促凋亡基因来阻断早期细胞凋亡也可以完全阻止 EMT，甚至抑制中胚层转化中最早的事件，包括 BRA/T、TBX6 和 MESP1 诱导。来自 WNT 激活的 WT iPSC 的条件培养基克服了无法凋亡的细胞 (Apop-) 对 EMT 的阻碍，表明来自凋亡细胞的可溶性因子参与了中胚层转化。 PANX1 通道的敲除会阻断 EMT，而用嘌呤能 P2 受体抑制剂或添加腺苷三磷酸双磷酸酶进行治疗则证明需要三磷酸核苷酸信号传导。 ATP和/或UTP足以在用WNT激活剂处理的Apop-细胞中诱导部分EMT。值得注意的是，敲除 ATP/UTP 特异性 P2Y2 受体会阻断 EMT 和中胚层诱导。我们得出的结论是，核苷酸除了充当清除凋亡细胞的化学引诱剂之外，还可以充当重要的旁分泌信号，与 WNT 信号一起为中胚层规范创建逻辑“与”门。
Pluripotent stem cells can be driven by manipulation of Wnt signaling through a series of states similar to those that occur during early embryonic development, transitioning from an epithelial phenotype into the cardiogenic mesoderm lineage and ultimately into functional cardiomyocytes. Strikingly, we observed that initiation of differentiation in induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) triggers widespread apoptosis, followed by a synchronous epithelial-mesenchymal transition (EMT). Apoptosis is caused by absence of bFGF from the differentiation medium. EMT requires induction of transcription factors SNAI1/SNAI2 downstream of MESP1 expression, and double knock-out of SNAI1/2, or loss of MESP1 in iPSCs blocks EMT and prevents cardiac differentiation. Remarkably, blockade of early apoptosis chemically or by ablation of pro-apoptotic genes also completely prevents the EMT, suppressing even the earliest events in mesoderm conversion, including BRA/T, TBX6, and MESP1 induction. Conditioned medium from WNT-activated WT iPSCs overcomes the block to EMT by cells incapable of apoptosis (Apop-), suggesting involvement of soluble factors from apoptotic cells in mesoderm conversion. Knockout of the PANX1 channel blocked EMT, while treatment with a purinergic P2 receptor inhibitor or addition of apyrase demonstrated a requirement for nucleotide triphosphate signaling. ATP and/or UTP was sufficient to induce a partial EMT in Apop- cells treated with WNT activator. Notably, knockout of the ATP/UTP-specific P2Y2 receptor blocked EMT and mesoderm induction. We conclude that nucleotides, in addition to acting as chemo-attractants for clearance of apoptotic cells can function as essential paracrine signals that, with WNT signaling, create a logical AND gate for mesoderm specification.
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影响因子：
11.8
作者：
Ankawa, Roi;Goldberger, Nitzan;Fuchs, Yaron
通讯作者：
Fuchs, Yaron
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Loh KM;Chen A;Koh PW;Deng TZ;Sinha R;Tsai JM;Barkal AA;Shen KY;Jain R;Morganti RM;Shyh-Chang N;Fernhoff NB;George BM;Wernig G;Salomon REA;Chen Z;Vogel H;Epstein JA;Kundaje A;Talbot WS;Beachy PA;Ang LT;Weissman IL
通讯作者：
Weissman IL
影响因子：
5.4
作者：
Turner DA;Rué P;Mackenzie JP;Davies E;Martinez Arias A
通讯作者：
Martinez Arias A
DOI：
10.1083/jcb.201007063
发表时间：
2011-03-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bondue A;Tännler S;Chiapparo G;Chabab S;Ramialison M;Paulissen C;Beck B;Harvey R;Blanpain C
通讯作者：
Blanpain C