Faculty, Staff and Student Publications

Language

English

Publication Date

3-2-2026

Journal

Journal of Experimental Medicine

DOI

10.1084/jem.20250607

PMID

41364073

PMCID

PMC12782086

PubMedCentral® Posted Date

3-2-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. Flow-responsive metabolic reprogramming depends upon mechanistic target of rapamycin (mTOR) activation and is stymied when ribosome activity or mTOR is blocked. Conversely, chemical induction of mTOR mimics the effects of force on mitochondria and blood reconstituting potential and also partially rescues hematopoiesis in heartbeat mutants in utero. These findings identify mechanometabolism as a determinant of hematopoietic fate that could inform engineering of HSCs for disease modeling and treatment.

Keywords

Hematopoietic Stem Cells, Animals, Mitochondria, Mice, Hematopoiesis, TOR Serine-Threonine Kinases, Stress, Mechanical, Cell Differentiation, Mice, Inbred C57BL, biomechanical force, blood flow, fate determination, hematopoietic stem cell, hemogenic endothelium, mechanometabolism, mitochondria, mTORC1, protein translation, ribosomes, 5’terminal polypyrimidine (TOP) motif, wall shear stress

Published Open-Access

yes

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