Canonical Wnt signaling promotes pacemaker cell specification of cardiac mesodermal cells derived from mouse and human embryonic stem cells.
Canonical Wnt signaling promotes pacemaker cell specification of cardiac mesodermal cells derived from mouse and human embryonic stem cells.
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DOI：
10.1002/stem.3106
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发表时间：
2020-03
期刊：
影响因子：
--
通讯作者：
Cho HC
中科院分区：
文献类型：
--
作者：
Liang W;Han P;Kim EH;Mak J;Zhang R;Torrente AG;Goldhaber JI;Marbán E;Cho HC
胚胎干细胞(ESCs)向心脏分化可分化为新生腔室心肌细胞和结节起搏细胞。与我们对直接分化为心房和心室肌细胞的理解相比，结节起搏细胞承诺的机制还不是很清楚。从典型的Wnt信号在鸡胚胎心脏起搏器组织发育过程中的突出作用中得到提示，我们询问Wnt信号的调制是否会影响心脏祖细胞分化为室性心肌细胞或起搏细胞。在小鼠和人ESCs分化过程中，省略外源性Wnt抑制剂(通常用于最大化心肌细胞产量)会导致自发搏动的心肌细胞产量增加，其动作电位特性与天然窦房结起搏细胞相似。伴随着起搏器表型的是标记结节起搏细胞的基因和基因产物的表达增强，如HCN4、TBX18、TBX3和Shox2。外源性Wnt3a配体的加入激活了典型的Wnt/β-catenin信号，增加了起搏样心肌细胞的产量，同时减少了cTnT阳性的泛心脏分化。相反，加入Wnt/β-连环蛋白信号的抑制剂会导致房室肌细胞谱系发育的增加，但以起搏细胞的规格为代价。经典的Wnt信号对结节起搏细胞分化的积极影响在两个人ESC系和人诱导的多能干细胞的直接分化中得到了证实。我们的数据证实Wnt/β-Catenin通路是胚胎干细胞分化过程中心肌细胞亚型承诺的关键决定因素：内源性Wnt信号有利于起搏器谱系，而其抑制促进腔心肌细胞谱系。
Cardiac differentiation of embryonic stem cells (ESCs) can give rise to de novo chamber cardiomyocytes and nodal pacemaker cells. Compared with our understanding of direct differentiation toward atrial and ventricular myocytes, the mechanisms for nodal pacemaker cell commitment are not well understood. Taking a cue from the prominence of canonical Wnt signaling during cardiac pacemaker tissue development in chick embryos, we asked if modulations of Wnt signaling influence cardiac progenitors to bifurcate to either chamber cardiomyocytes or pacemaker cells. Omitting an exogenous Wnt inhibitor, which is routinely added to maximize cardiac myocyte yield during differentiation of mouse and human ESCs, led to increased yield of spontaneously beating cardiomyocytes with action potential properties similar to those of native sinoatrial node pacemaker cells. The pacemaker phenotype was accompanied by enhanced expression of genes and gene products that mark nodal pacemaker cells such as Hcn4, Tbx18, Tbx3, and Shox2. Addition of exogenous Wnt3a ligand, which activates canonical Wnt/β-catenin signaling, increased the yield of pacemaker-like myocytes while reducing cTNT-positive pan-cardiac differentiation. Conversely, addition of inhibitors of Wnt/β-catenin signaling led to increased chamber myocyte lineage development at the expense of pacemaker cell specification. The positive impact of canonical Wnt signaling on nodal pacemaker cell differentiation was evidenced in direct differentiation of two human ESC lines and human induced pluripotent stem cells. Our data identify the Wnt/β-catenin pathway as a critical determinant of cardiac myocyte subtype commitment during ESC differentiation: endogenous Wnt signaling favors the pacemaker lineage, whereas its suppression promotes the chamber cardiomyocyte lineage.
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影响因子：
3.7
作者：
Groenke S;Larson ED;Alber S;Zhang R;Lamp ST;Ren X;Nakano H;Jordan MC;Karagueuzian HS;Roos KP;Nakano A;Proenza C;Philipson KD;Goldhaber JI
通讯作者：
Goldhaber JI
影响因子：
7.2
作者：
Cruciat, Cristina-Maria;Niehrs, Christof
通讯作者：
Niehrs, Christof
影响因子：
4.6
作者：
Cohen, Ethan David;Miller, Mayumi F.;Morrisey, Edward E.
通讯作者：
Morrisey, Edward E.
影响因子：
2.5
作者：
Christoffels, VM;Hoogaars, WMH;Campione, M
通讯作者：
Campione, M
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.