Jackson, Timothy Ryan
(2017)
The Interplay of Biomechanics, Tissue Polarity and Collective Migration as it Contributes to Early Heart Organogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In early heart development, bilateral fields of heart progenitor cells (HPCs) undergo a large-scale movement from the anterior lateral plate mesoderm to merge on the ventral midline, undergoing a mesenchymal-to-epithelial transition (MET) halfway through this process. While the heart is the first functioning organs in the developing embryo, a comprehensive model for early heart development that integrates both physical mechanisms and molecular signaling pathways remains elusive. Here, we utilize Xenopus embryos to investigate the role of mechanical cues in driving MET in HPCs and show how dysregulation of these cues can cause congenital heart defects (CHDs).
Small molecule inhibitor treatments targeting actomyosin contractility reveal a temporally specific requirement of bulk tissue compliance to regulate heart development and MET. 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 the onset of MET correlates with a peak in mechanical stress within the HFR and changes in HPC migratory behaviors. Targeting mutant constructs to modulate contractility and compliance in the underlying endoderm, we find MET in HPCs can be accelerated in response to microenvironmental stiffening and can be inhibited by softening. To test whether MET in HPCs is 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 is sufficient to drive MET. MET-induced defects in anatomy result in defined functional lesions in the larval heart and furthermore, when we recreate a clinically-relevant CHD phenotype through overexpression of a Noonan Syndrome-associated mutant protein, we find it leads to abnormal MET in HPCs due to a decoupling of force transmission and mechanosensory pathways.
From this integrated analysis of HPC polarity and mechanics, we propose that normal heart development requires 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. We conclude that the etiology underlying many CHDs may involve errors in mechanical signaling and MET.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
14 June 2017 |
| Date Type: |
Publication |
| Defense Date: |
15 March 2017 |
| Approval Date: |
14 June 2017 |
| Submission Date: |
28 March 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
311 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
heart development, mesenchymal-to-epithelial transition, biomechanics, Xenopus |
| Date Deposited: |
14 Jun 2017 15:53 |
| Last Modified: |
14 Jun 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30975 |
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