2. Academic Validation
  3. Mechanometabolism instructs hematopoietic stem cell specification

Mechanometabolism instructs hematopoietic stem cell specification

  • J Exp Med. 2026 Mar 2;223(3):e20250607. doi: 10.1084/jem.20250607.
Paulina D Horton 1 2 3,  Alina Syed 1,  Michelle Winkler 1 3,  Abishek B Vaidya 2,  Michael Rariden 2,  Neha Arora 1,  Yong Zhou 1 4,  Michihiro Kobayashi 2,  Momoko Yoshimoto 2,  Hyun Jung Lee 5 6,  Hyun-Eui Kim 1 4,  John P Hagan 4 7,  Catherine Denicourt 1 4,  Travis I Moore 1 4,  Pamela L Wenzel 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 2 Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston , Houston, TX, USA.
  • 3 Immunology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences , Houston, TX, USA.
  • 4 Molecular and Translational Biology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences , Houston, TX, USA.
  • 5 Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, South Korea.
  • 6 Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, South Korea.
  • 7 Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
PMID: 41364073 DOI: 10.1084/jem.20250607
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.

Figures
Products