Investigating metabolic and mitochondrial adaptations triggered by blood flow during the endothelial-to-hematopoietic transition

<p>Hematopoietic stem cell (HSC) transplant is the standard of care for many hematologic diseases. However, many patients cannot benefit from this potentially curative treatment because they cannot find a suitable donor, contributing to a high level of unmet need. Recently, bona fide<em> </em>HSCs capable of robust engraftment and differentiation have been generated from iPSCs utilizing wall shear stress (WSS) to help promote HSC generation. However, the mechanisms through which WSS regulates hematopoiesis remain poorly understood. Scientists, therefore, continue to look for the mechanotransduction pathways that promote hematopoiesis, and key answers may lie in examining the role of extrinsic factors that regulate hematopoiesis in the developing embryo.</p> <p>We show that the physical forces associated with blood flow are critical for regulating metabolic shifts necessary for the specification of HSCs emerging from arterial vessels during embryogenesis. Mutant embryos lacking a heartbeat fail to produce HSCs and only have hematopoietic precursors with immature mitochondria containing fewer cristae, as determined by electron microscopy. Force generated by blood flow stimulates mitochondrial protein translation, cristae formation, increased mitochondrial membrane potential, and oxidative phosphorylation. These adaptations can be mimicked <em>ex vivo </em>by exposing cultured hematopoietic precursors to force, resulting in increased mitochondrial activity with improved transplantation performance. Single-cell transcriptome and protein analyses indicate that force-responsive PI3K-Akt signaling regulates mTORC1 effectors S6K and 4E-BP1 to promote translation of mitochondrial ribosomes and electron transport chain proteins.</p> <p>Our work exposes an overlooked role of force in the maturation of mitochondrial machinery essential for HSC emergence and population of the blood system. Our study provides clues to essential flow-sensitive molecular mechanisms that can be leveraged for future HSC engineering.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Horton, Paulina
• <p><a href="http://www.orcid.org/0000-0002-5190-569X" target="_blank">http://www.orcid.org/0000-0002-5190-569X</a></p>

Contributors dc:contributor

• Pamela Wenzel
• Joya Chandra
• Momoko Yoshimoto

• Hematopoiesis
• Biomechanical force
• Protein synthesis
• mTOR
• Metabolism
• Mitochondrial dynamics
• Hematopoietic stem cells
• Developmental biology
• Molecular Biology
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1457

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2514