Intrinsic cellular chirality regulates left-right symmetry breaking during cardiac looping.
Intrinsic cellular chirality regulates left-right symmetry breaking during cardiac looping.
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DOI：
10.1073/pnas.1808052115
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发表时间：
2018-12-11
影响因子：
11.1
通讯作者：
Wan LQ
中科院分区：
文献类型：
--
作者：
Ray P;Chin AS;Worley KE;Fan J;Kaur G;Wu M;Wan LQ
细胞手性，或细胞的手性，是一个新发现的细胞的基本特性，到目前为止，在细胞培养中只研究了微图案或基于梯度生物材料的方法。细胞内在手性与器官侧性的相关性尚未确定。心环是胚胎发生过程中第一个明显的器官特异性左右不对称。尽管对调节心脏左右不对称的分子信号有了广泛的了解，但其生物物理机制仍不清楚。我们的发现建立了内在的细胞手性作为心脏侧性的调节。本研究将体外手性测定与体内胚胎左右不对称相结合，将对胚胎左右不对称与先天性心脏病的认识和未来研究产生重大影响。脊椎动物的身体平面是整体对称的，但内部器官的形状和位置是左右不对称的。虽然已经提出了几种理论，但LR不对称的生物物理机制仍然不清楚，特别是细胞手性，细胞水平上的LR不对称，对器官不对称的作用。在发育中的鸡胚胎中，我们研究了内在的细胞手性或手性是否调节心脏C环。利用最近建立的基于生物材料的3D培养平台，我们证明了鸡心脏细胞在C环形成之前和过程中具有内在的手性，并在体外表现出主要的顺时针旋转。我们进一步表明，发育中的心肌细胞具有手性，这一点可以通过细胞排列的向右偏置和高尔基复合体的向右极化来证明，这与心管旋转的方向有关。此外，在心环发生前，N-cadherin和myosin II在心肌中存在LR极化分布。更有趣的是，通过激活蛋白激酶C信号通路逆转的细胞手性逆转了心脏环的方向性，并伴随着心管上细胞偏差的逆转。我们的研究结果表明，心肌细胞手性调节了心管中细胞LR对称性的破坏以及由此产生的心环的方向性。我们的研究提供了证据，证明在脊椎动物发育过程中，在定向组织旋转过程中，固有的细胞手性偏倚导致LR对称性破坏。
Cell chirality, or handedness of the cell, is a newly discovered, fundamental property of the cell, so far studied in cell culture only with micropatterning or graded biomaterial-based approaches. The relevance of intrinsic cell chirality on organ laterality is yet to be established. Cardiac looping is the first organ-specific left–right asymmetry evident during embryogenesis. Despite extensive insights into the molecular signals regulating cardiac left–right asymmetry, the biophysical mechanism is still unknown. Our findings establish intrinsic cell chirality as a regulator of cardiac laterality. This study combines an in vitro chirality assay with embryonic left–right asymmetry in vivo and will significantly impact the understanding and future studies of embryonic left–right asymmetry and congenital heart diseases. The vertebrate body plan is overall symmetrical but left–right (LR) asymmetric in the shape and positioning of internal organs. Although several theories have been proposed, the biophysical mechanisms underlying LR asymmetry are still unclear, especially the role of cell chirality, the LR asymmetry at the cellular level, on organ asymmetry. Here with developing chicken embryos, we examine whether intrinsic cell chirality or handedness regulates cardiac C looping. Using a recently established biomaterial-based 3D culture platform, we demonstrate that chick cardiac cells before and during C looping are intrinsically chiral and exhibit dominant clockwise rotation in vitro. We further show that cells in the developing myocardium are chiral as evident by a rightward bias of cell alignment and a rightward polarization of the Golgi complex, correlating with the direction of cardiac tube rotation. In addition, there is an LR polarized distribution of N-cadherin and myosin II in the myocardium before the onset of cardiac looping. More interestingly, the reversal of cell chirality via activation of the protein kinase C signaling pathway reverses the directionality of cardiac looping, accompanied by a reversal in cellular biases on the cardiac tube. Our results suggest that myocardial cell chirality regulates cellular LR symmetry breaking in the heart tube and the resultant directionality of cardiac looping. Our study provides evidence of an intrinsic cellular chiral bias leading to LR symmetry breaking during directional tissue rotation in vertebrate development.
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DOI：
10.1152/ajpheart.1997.273.3.h1113
发表时间：
1997-09-01
影响因子：
4.8
作者：
Deng, XF;Mulay, S;Varma, DR
通讯作者：
Varma, DR
DOI：
10.1152/ajpcell.1997.273.3.c937
发表时间：
1997-09-01
影响因子：
5.5
作者：
Liedtke, CM;Cole, T;Ikebe, M
通讯作者：
Ikebe, M
影响因子：
4.5
作者：
Lenhart KF;Holtzman NG;Williams JR;Burdine RD
通讯作者：
Burdine RD
影响因子：
2.7
作者：
Chocron, Sonja;Verhoeven, Manon C.;Bakkers, Jeroen
通讯作者：
Bakkers, Jeroen
影响因子：
20.1
作者：
Geraldes P;King GL
通讯作者：
King GL