A Notch <i>trans-</i> activation to <i>cis</i> -inhibition switch underlies hematopoietic stem cell aging
Abstract
Abstract 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 on 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.
Article Details
Authors (13)
Francesca Matteini
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain
Roshana Thambyrajah
3Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain
Sara Montserrat-Vazquez
Sascha Jung
6Center for Cooperative Research in Biosciences–Basque Research and Technology Alliance, Bizkaia Technology Park, Derio, Spain
Alba Ferrer-Perez
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain
Patricia Herrero Molinero
3Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain
Dina El Jaramany
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain
Javier Lozano-Bartolomé
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain
Eva Mejia-Ramirez
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain
Jessica González
Antonio Del Sol
Anna Bigas
Maria Carolina Florian
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain