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All stressed out: physical tension drives mesenchymal‐to‐epithelial transition in heart progenitor cells
Author(s) -
Davidson Lance,
Jackson Timothy R,
Kim Hye Young
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.242.2
Subject(s) - mesenchymal stem cell , microbiology and biotechnology , zebrafish , contractility , anatomy , progenitor cell , biology , mesoderm , xenopus , heart development , chemistry , stem cell , embryonic stem cell , endocrinology , genetics , gene
Proper heart formation involves coordinated movements by endoderm and mesenchymal heart progenitor cells (HPCs). Bilateral populations of HPCs begin these movements as mesenchymal cells but transition to epithelial before they form the ventral heart trough. Originating from the lateral plate mesoderm in the frog Xenopus laevis HPCs first localize aPKC to a putative apical surface then assemble apical junctions rich in ZO‐1 well in advance of reaching the ventral midline. Ex vivo and intra vital imaging reveals that cells undergoing MET exhibit stereotypical changes in collective migration and traction forces. This “phase‐transition” supports observations in chicken and zebrafish and suggest that mesenchymal HPCs are initially carried to the midline by endoderm but complete their movements as epithelia via traction‐mediated migration. To understand the role of mechanics in the spatial and temporal control of this mesenchymal‐to‐epithelial transition (MET) we carried out a biomechanical analysis of the heart forming region (HFR). Time‐lapse imaging of the HFR reveals a complex pattern of shape change, first contracting in the anterior‐posterior direction then elongating. Strain maps from this analysis combined with biomechanical measurements of tissue compliance with microaspiration reveal MET coincides with peak levels of tissue stress in the HFR suggesting mechanical cues from the microenvironment are responsible for inducing MET in the HPCs. To test such a role for tissue stress we took three different approaches to modulating mechanics: 1) overexpression of constitutive active Rho‐GEF, 2) incubation with activators and inhibitors of cell contractility, and 3) exogenously applied strain. Overexpression of contractility by targeted mRNA injections revealed that MET could be driven non‐cell autonomously by stiffening endoderm. Transient disruptions in MET with small molecule inhibitors and activators of contractility revealed decreased contractility could inhibit while increased contractility could precociously induce MET. Finally, using only physical means to strain the HFR we were also able to induce early MET. Each of these three perturbations of the mechanical microenvironment resulted in specific defects in the architecture of the larval heart which manifest in defects in cardiac output. Thus, using biophysical and cell biological methods we identified endogenous changes in the mechanical microenvironment in the heart forming region (HFR) that appear to drive HPCs into a mesenchymal‐to‐epithelial transition and how lesions in that regulation impact heart structure and function. Support or Funding Information National Science Foundation (CBET‐1547790), National Institutes of Health (R01HD044750; R56HL13495) and the Cardiovascular Bioengineering Training Program (NIH NHLBI T32 HL076124).