Investigating Metabolic and Mitochondrial Adaptations Triggered by Blood Flow During the Endothelial-to-Hematopoietic Transition

Paulina Horton (Advisor: Pamela Wenzel, PhD)

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. Attempts have been made to generate HSCs in vitro, but so far none of these attempts have produced bona fide HSCs suitable for transplant. Scientists continue to look for signals from the niche that promote hematopoiesis, and key answers may lie in examining the role of extrinsic factors that regulate hematopoiesis in the developing embryo.

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 progenitors with immature mitochondria containing fewer cristae, as determined by electron and super-resolution microscopy. Force generated by blood flow stimulates mitochondrial protein translation, cristae formation, increased mitochondrial membrane potential, and oxidative phosphorylation. These adaptations can be mimicked ex vivo by exposing cultured hematopoietic progenitors 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.

Our work exposes an overlooked role of force in the maturation of mitochondrial machinery essential for HSC emergence and population of the blood system. While in vitro specification of HSCs continues to elude us, our study may provide clues to essential flow-sensitive molecular mechanisms that can be leveraged for future HSC engineering.

Advisory Committee:

• Pamela Wenzel, PhD, Chair
• Joya Chandra, PhD
• Jin Seon Im, MD, PhD
• Hyun-Eui Kim, PhD
• Momoko Yoshimoto, PhD
• Kartik Venkatachalam, PhD

Join via Zoom (NOTE: Please contact Ms. Paulina Horton for her Zoom meeting info.)