Hypercholesterolaemia induces the expansion of haematopoietic stem and progenitor cells (HSPCs), resulting in increased leukocyte numbers, which contribute to atherosclerotic cardiovascular disease. However, the mechanisms linking hypercholesterolaemia and HSPC expansion are unclear. Longhou Fang and colleagues describe a new mechanism for HSPC emergence in embryogenesis that also regulates adult haematopoiesis in hypercholesterolaemic conditions.
The investigators show that during embryogenesis in zebrafish, apolipoprotein A-I binding protein 2 (Aibp2; also known as Yjefn3) — a pro-haematopoietic cue derived from the somite that binds to HDL, which augments cholesterol efflux — increases HSPC specification from the haemogenic endothelium through the activation of sterol regulatory element-binding protein 2 (Srebp2), the master regulator of cholesterol biosynthesis. Aibp2-mediated cholesterol efflux activates endothelial Srebp2, which in turn transactivates the Notch pathway, promoting HSPC emergence.
In Ldlr-knockout mice fed a high-cholesterol diet, inhibition of SREBP2 repressed the hypercholesterolaemia-induced HSPC expansion in the bone marrow, suggesting that SREBP2-regulated Notch signalling contributes to HSPC expansion during hypercholesterolaemia in adults. Previous studies in mice showed that SREBP2 inhibition reduces atherosclerotic burden. “We speculate that SREBP2 suppression protects against cardiovascular disease in part by targeting aberrant haematopoiesis,” explains Fang.
Finally, the investigators confirmed the relevance of their findings in humans, showing that increased SREBP2 and Notch signalling activation was associated with HSPC expansion in patients with hypercholesterolaemia.
“SREBP2-regulated Notch signalling contributes to HSPC expansion during hypercholesterolaemia”
The research team plans to continue exploring the role of cholesterol metabolism in haematopoiesis. “Generation of autologous, bona fide HSPCs is essential for regenerative medicine, and our findings may bring us one step closer to this ultimate goal,” highlights Fang. “Our studies also provide new therapeutic targets for immunological and haematological diseases, as well as for cardiovascular disease.”
Gu, Q. et al. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science 363, 1085–1088 (2019)
Rahman, M. S. et al. Effects of dyslipidaemia on monocyte production and function in cardiovascular disease. Nat. Rev. Cardiol. 14, 387–400 (2017)
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Fernández-Ruiz, I. Cholesterol efflux drives stem cell expansion in hypercholesterolaemia. Nat Rev Cardiol 16, 323 (2019). https://doi.org/10.1038/s41569-019-0187-0