Aging is the primary risk factor for many human pathologies. Therefore, understanding aging and counteracting the decline in physiological functions represents a promising strategy to increase health and lifespan. One of the major hallmarks of aging is stem cell exhaustion. In the case of blood stem cells, cell exhaustion and clonal expansion over time reduces their regenerative capacity and leads to the inability of the aged haematopoietic system to maintain homeostasis. Importantly, mounting evidence supports that the haematopoietic system might be driving healthspan and lifespan of the whole organism, as stated by Dr M. Carolina Florian last September in Nature Cell Biology. The stem cell ageing research group at IDIBELL, led by ICREA research professor Dr Florian, is working to define strategies that rejuvenate blood stem cells with the ultimate aim of improving overall health. Now, they published results that could open a new path towards this.

Notch signalling in blood stem cell aging

Notch signalling plays a pivotal role in haematopoietic stem cell (HSC) development: first, it promotes HSC development during embryogenesis, and, after birth, its downregulation ensures definitive hematopoiesis – correct blood stem cell formation. Despite several evidence on Notch signalling regulating HSC regenerative capacity, its exact role during HSC aging was still far from being completely understood. Now, RegenBell researchers have filled this gap of knowledge. They revealed the role of the bone marrow vasculature in regulating Notch’s capacity to act as a switch from extrinsic activation to intrinsic inhibition, ultimately regulating HSC aging.

As explained in their recent publication in Blood, RegenBell researchers conducted specific in vivo assays and a highly sensitive 3D-quantitative histological approach (iFAST3D) to analyse cell localization and interactions. They observed that Notch signalling is not homogeneously activated among all HSCs. There is a specific HSC group located next to the bone marrow vasculature where Notch signalling is maintained active by the expression of Jag2 from these vasculature endothelial cells. Florian’s team performed experiments to show how Jag2 activates Notch in HSCs, regulates their localization and sustains HSCs long-term regenerative capacity. Moreover, they observed that Jag2 deletion in the bone marrow vasculature has detrimental effects on HSC function and division, accelerating stem cell ageing.

As RegenBell researcher and first author of the study Dr Francesca Matteini puts it, “Collectively we demonstrate a key role of Notch signalling in HSCs aging, all mediated by Jag2. Our data shows that a crosstalk between the bone marrow vasculature and HSCs contributes to the maintenance of haematopoiesis throughout life, paving the way to a novel targeted-approach to counteract blood aging.”

This research counted on funding by the European Research Council (ERC) grant ReSinAge101002453 and LaCaixa Health Research grant HR20-00800.