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The hematopoietic stem cells or HSCs are multipotent, meaning they can differentiate and give rise to all blood and immune cells. HSCs are maintained in the quiescent stage until an external stimulus initiates their differentiation. The multipotent HSCs exist as two heterogeneous populations, long-term repopulating cells (LTRC) and short-term repopulating cells (STRC). The two HSC populations have different surface markers or receptors and are classified based on quiescence and long-term...
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Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells.

Eva Mejía-Ramírez1,2,3, Pablo Iáñez Picazo4,5, Barbara Walter1,2

  • 1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Nature Aging
|November 25, 2025
PubMed
Summary
This summary is machine-generated.

Aging hematopoietic stem cells (HSCs) show reduced regeneration due to increased nuclear tension. Inhibiting RhoA activity restores youthful HSC function by reducing this tension and improving cell regeneration.

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Area of Science:

  • Stem cell biology
  • Mechanobiology
  • Aging research

Background:

  • Hematopoietic stem cell (HSC) regenerative capacity declines with age.
  • Biomechanical changes and mechanosignaling alterations are implicated in HSC aging.
  • The role of RhoA in HSC mechanotransduction during aging is not well understood.

Purpose of the Study:

  • To investigate the role of RhoA in HSC mechanotransduction and aging.
  • To elucidate the mechanisms linking nuclear envelope tension to RhoA activation in aged HSCs.
  • To determine if targeting RhoA can restore aged HSC function.

Main Methods:

  • Analysis of nuclear envelope (NE) tension in murine HSCs.
  • Investigating the translocation of P-cPLA2 and RhoA activation.
  • Utilizing feature image analysis of HSC nuclei for chromatin remodeling assessment.
  • Evaluating the impact of RhoA inhibition on HSC regenerative capacity and lympho/myeloid output in vivo.

Main Results:

  • Aged HSCs exhibit increased intrinsic NE tension, activating RhoA via P-cPLA2 translocation.
  • Reducing RhoA activity in aged HSCs decreases NE tension and promotes chromatin remodeling.
  • RhoA inhibition restores youthful H3K9me2 levels, reduces chromatin accessibility at retrotransposons, and upregulates Klf4.
  • Pharmacological inhibition of RhoA improves aged HSC regenerative capacity and lymphoid/myeloid balance in vivo.

Conclusions:

  • An intrinsic RhoA-dependent mechanosignaling axis regulates aged HSC function.
  • Targeting RhoA can restore the regenerative capacity of aged stem cells.
  • This study provides a potential therapeutic strategy for age-related stem cell dysfunction.