A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.

[en] Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.

Disciplines :

Life sciences: Multidisciplinary, general & others

Author, co-author :

Matteini, Francesca ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

Thambyrajah, Roshana; Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain

Montserrat-Vazquez, Sara ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

JUNG, Sascha ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine ; CIC bioGUNE-BRTA (Basque Research and Technology Alliance), 5Ikerbasque, Basque Foundation for Science, Derio, Spain

Ferrer-Perez, Alba ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

Herrero Molinero, Patricia ; Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain

El Jaramany, Dina ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

Lozano-Bartolomé, Javier ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

Mejia-Ramirez, Eva ; The Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Spain

Gonzalez Miranda, Jessica ; Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain

More authors (3 more)

External co-authors :

yes

Language :

English

Title :

A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.

Publication date :

07 October 2025

Journal title :

Blood

ISSN :

0006-4971

eISSN :

1528-0020

Publisher :

American Society of Hematology, United States

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2024026505/2415620/blood.2024026505.pdf

Available on ORBilu :

since 08 October 2025

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