Labs: Kenichi Miharada

Paper information

Title:

Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions

Saito K, van der Garde M, Umemoto T, Miharada N, Sjöberg J, Sigurdsson V, Shirozu H, Kamei S, Radulovic V, Suzuki M, Nakano S, Lang S, Hansson J, Olsson ML, Minami T, Gouras G, Flygare J, Miharada K.

Nature Communications September 16 Volume 15, Page 8131 (2024). doi: https://doi.org/10.1038/s41467-024-52509-w

URL: https://www.nature.com/articles/s41467-024-52509-w

Highlights

• Upon acute anemia induction, not only committed erythroid precursors but also hematopoietic stem cells (HSCs) rapidly proliferate and become prone to producing erythroid cells.
• Under severe anemia conditions, apolipoprotein E increases and binds to VLDL-receptor on HSCs, causing genetic and epigenetic changes.
• The results of this study are expected to lead to the development of new treatments for severe anemia, which has been difficult to treat at present.

Abstract:

Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. Vldlr^highHSCs show higher erythroid potential, which is enhanced after acute anemia induction. Vldlr^highHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays an important role in HSC regulation under severe anemic conditions.