BRM preserves sinusoidal niche resilience through Jag2-Notch signaling during hematopoietic regeneration and aging
- 1Kobe University Graduate School of Medicine
Abstract
During aging and stress, remodeling of the bone marrow (BM) microenvironment compromises hematopoietic stem cell (HSC) maintenance, contributing to extrinsic HSC aging. Although niche-derived Notch signaling is essential for hematopoietic regeneration following myelosuppressive injury, the upstream chromatin regulatory mechanisms governing this stress-responsive signaling remain poorly understood. Here, we identify the chromatin remodeler BRM as a critical regulator of the BM sinusoidal niche integrity and hematopoietic regeneration. Using reciprocal BM transplantation, we demonstrate that a Brm-deficient microenvironment impairs hematopoietic reconstitution and imposes an aging-like myeloid bias characterized by expansion of granulocyte-monocyte progenitors. Following 5-fluorouracil (5-FU)-induced myelosuppression, BrmKO mice exhibit defective sinusoidal regeneration accompanied by endothelial degeneration. Mechanistically, BRM deficiency compromises Notch signaling at two levels: it reduces the Jag2 ligand pool through persistent depletion of sinusoidal endothelial cells (SECs) and impaired regenerative expansion of Jag2-producing LepR+ stromal cells, while also impairing stress-induced Notch2 expression and downstream Hes1 activation in SECs. These defects are accompanied by impaired sinusoidal regeneration and failure to restore normal HSC positioning relative to the sinusoidal vasculature. Notably, the Brm-deficient microenvironment recapitulates key features of physiological niche aging, while BRM expression declines with age in SECs. Collectively, our findings identify BRM as a key regulator of BM niche regenerative resilience and suggest that age-associated BRM decline contributes to niche dysfunction and hematopoietic aging.
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BibTeX
@misc{suzuki2026preserves,
title = {{BRM preserves sinusoidal niche resilience through Jag2-Notch signaling during hematopoietic regeneration and aging}},
author = {H. Suzuki and H. Miyachi and N. Yamada and H. Nishikawa and S. Kuno and H. Endoh and T. Shiina and R. Yoshikawa and S. Uemura and A. Iwama and T. Suda and R. Nitta and E. Nitta},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.03.736310},
url = {https://www.biorxiv.org/content/10.64898/2026.07.03.736310v3},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - BRM preserves sinusoidal niche resilience through Jag2-Notch signaling during hematopoietic regeneration and aging
AU - H. Suzuki
AU - H. Miyachi
AU - N. Yamada
AU - H. Nishikawa
AU - S. Kuno
AU - H. Endoh
AU - T. Shiina
AU - R. Yoshikawa
AU - S. Uemura
AU - A. Iwama
AU - T. Suda
AU - R. Nitta
AU - E. Nitta
PY - 2026
DA - 2026/07/03
PB - bioRxiv
DO - 10.64898/2026.07.03.736310
UR - https://www.biorxiv.org/content/10.64898/2026.07.03.736310v3
AB - During aging and stress, remodeling of the bone marrow (BM) microenvironment compromises hematopoietic stem cell (HSC) maintenance, contributing to extrinsic HSC aging. Although niche-derived Notch signaling is essential for hematopoietic regeneration following myelosuppressive injury, the upstream chromatin regulatory mechanisms governing this stress-responsive signaling remain poorly understood. Here, we identify the chromatin remodeler BRM as a critical regulator of the BM sinusoidal niche integrity and hematopoietic regeneration. Using reciprocal BM transplantation, we demonstrate that a Brm-deficient microenvironment impairs hematopoietic reconstitution and imposes an aging-like myeloid bias characterized by expansion of granulocyte-monocyte progenitors. Following 5-fluorouracil (5-FU)-induced myelosuppression, BrmKO mice exhibit defective sinusoidal regeneration accompanied by endothelial degeneration. Mechanistically, BRM deficiency compromises Notch signaling at two levels: it reduces the Jag2 ligand pool through persistent depletion of sinusoidal endothelial cells (SECs) and impaired regenerative expansion of Jag2-producing LepR+ stromal cells, while also impairing stress-induced Notch2 expression and downstream Hes1 activation in SECs. These defects are accompanied by impaired sinusoidal regeneration and failure to restore normal HSC positioning relative to the sinusoidal vasculature. Notably, the Brm-deficient microenvironment recapitulates key features of physiological niche aging, while BRM expression declines with age in SECs. Collectively, our findings identify BRM as a key regulator of BM niche regenerative resilience and suggest that age-associated BRM decline contributes to niche dysfunction and hematopoietic aging.
ER -