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Curr Biol May 8, 2017; 27 (9): 1326-1335.

Spatiotemporally Controlled Mechanical Cues Drive Progenitor Mesenchymal-to-Epithelial Transition Enabling Proper Heart Formation and Function.

Jackson TR , Kim HY , Balakrishnan UL , Stuckenholz C , Davidson LA .

During early cardiogenesis, bilateral fields of mesenchymal heart progenitor cells (HPCs) move from the anterior lateral plate mesoderm to the ventral midline, undergoing a mesenchymal-to-epithelial transition (MET) en route to forming a single epithelial sheet. Through tracking of tissue-level deformations in the heart-forming region (HFR) as well as movement trajectories and traction generation of individual HPCs, we find that the onset of MET correlates with a peak in mechanical stress within the HFR and changes in HPC migratory behaviors. Small-molecule inhibitors targeting actomyosin contractility reveal a temporally specific requirement of bulk tissue compliance to regulate heart development and MET. Targeting mutant constructs to modulate contractility and compliance in the underlying endoderm, we find that MET in HPCs can be accelerated in response to microenvironmental stiffening and can be inhibited by softening. To test whether MET in HPCs was responsive to purely physical mechanical cues, we mimicked a high-stress state by injecting an inert oil droplet to generate high strain in the HFR, demonstrating that exogenously applied stress was sufficient to drive MET. MET-induced defects in anatomy result in defined functional lesions in the larval heart, implicating mechanical signaling and MET in the etiology of congenital heart defects. From this integrated analysis of HPC polarity and mechanics, we propose that normal heart development requires bilateral HPCs to undergo a critical behavioral and phenotypic transition on their way to the ventral midline, and that this transition is driven in response to the changing mechanical properties of their endoderm substrate.

PubMed ID: 28434863
PMC ID: PMC5497766
Article link: Curr Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: arhgef2 ctnnb1 fbn1 fn1 grap2 prkci tjp1 tnnt2 tpm1
GO keywords: heart development [+]
Antibodies: Fbn2 Ab1 Fn1 Ab1 Tnnt2 Ab1 Tpm1 Ab1

Article Images: [+] show captions
References [+] :
Abualsaud, Cardiac output as a predictor in congenital heart disease: Are we stating the obvious? 2016, Pubmed