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The Crosstalk of Biomechanical and Biochemical Cues in Endothelial Cell – Interactions of Shear Stress to ALK1 Signaling and Geometric Confinement

Cheng, Ya-Wen (2023) The Crosstalk of Biomechanical and Biochemical Cues in Endothelial Cell – Interactions of Shear Stress to ALK1 Signaling and Geometric Confinement. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Mechanical cues and biochemical stimulations impact cell functions throughout the body. We investigate how these mechanical and biochemical factors influence endothelial cells' behaviors and how they contribute to arteriovenous malformations (AVMs), which are often associated with hereditary hemorrhagic telangiectasia (HHT). There is evidence that AVMs are likely caused by irregular endothelial cell (EC) migration, but how ALK1-ligands and biophysical cues influence EC migration or morphology is not well known. To understand the origins of HHT and AVMs, we study EC behavior changes in response to biomechanical and biochemical cues.
To better understand the role of Activin receptor-like kinase 1 (ALK1) in EC mechanosensing through wall shear stress (SS) and ALK1-ligand cues, we develop a custom microfluidic device and automated image analysis pipeline to measure EC response to these cues at a single-cell level. We confirm SS and BMP9 ligands have synergistic effects, and resolve similar synergy between SS and BMP10 and BMP9/10 heterodimers. Furthermore, we find that SS induces an ultra-low ligand response. We also demonstrate that the ALK1 receptor plays a crucial role in SMAD signaling synergy between SS and ALK signaling, and the involvement of endocytosis in the ultra-low ligand mechanosensory pathway.
To investigate how geometric confinement affects EC migration and polarity when SS is present, we developed a novel microfluidic device with different channel widths to alter confinement and variable height to maintain a constant SS. Our results show that flow-mediated SS increases cell migration speed and polarization; fewer cells migrate and polarize downstream near the lateral edge, suggesting that cells located near the lateral edge were induced to move against the flow. We conclude that distance from the lateral edge determines polarity and migration more than width change.
Our study provides insights into how ALK1 signaling, shear stress, and geometric confinement interact to regulate EC migration behavior under normal and disease-like conditions. Moreover, our microchips offer systematic in-vitro models for biomechanical and biophysical studies with well-controlled SS magnitudes, SS gradients, and confinement. Our research contributes to the development of medical therapies for the treatment of HHT patients [RBL1] and other types of cardiovascular disease by enhancing our understanding of how ECs respond to biomechanical and biochemical cues.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cheng, Ya-Wenyac50@pitt.eduyac500000-0001-8162-1690
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDavidson, Lance A.lad43@pitt.edulad43
Committee MemberRoman, Beth L.romanb@pitt.eduromanb
Committee MemberPartha, Roypar19@pitt.edupar19
Committee MemberPrithu, Sunddprs51@pitt.eduprs51
Committee MemberYu-Li, Wangyuliwang@andrew.cmu.edu
Date: 14 September 2023
Date Type: Publication
Defense Date: 7 April 2023
Approval Date: 14 September 2023
Submission Date: 12 April 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 185
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: endothelial cell biology endothelial cell polarity mechanotransduction mechanobiology mechanosensing pSMAD1/5/8 ALK1 receptor trafficking
Date Deposited: 14 Sep 2023 13:33
Last Modified: 14 Sep 2023 13:33
URI: http://d-scholarship.pitt.edu/id/eprint/44692

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  • The Crosstalk of Biomechanical and Biochemical Cues in Endothelial Cell – Interactions of Shear Stress to ALK1 Signaling and Geometric Confinement. (deposited 14 Sep 2023 13:33) [Currently Displayed]

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