Bmi1 Suppresses Adipogenesis in the Hematopoietic Stem Cell Niche

• Published in: Stem cell reports Vol. 13; no. 3; pp. 545 - 558
• Main Authors: Hu, Tianyuan, Kitano, Ayumi, Luu, Victor, Dawson, Brian, Hoegenauer, Kevin A., Lee, Brendan H., Nakada, Daisuke
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2019; Elsevier
• Subjects: adipocytes; BMI1; epigenetics; hematopoietic stem cells; mesenchymal stromal cells; niche; PAX3; polycomb; mesenchymal stromal cells; polycomb; PAX3; niche; BMI1; hematopoietic stem cells; adipocytes; epigenetics
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.05.027

Bone marrow stromal cells (BMSCs) that express high levels of stem cell factor (SCF) and CXC chemokine ligand 12 (CXCL12) are one crucial component of the hematopoietic stem cell (HSC) niche. While the secreted factors produced by BMSCs to support HSCs have been well described, little is known regarding the transcriptional regulators controlling the cell fate of BMSCs and thus indirectly maintaining HSCs. BMI1 is a polycomb group protein that regulates HSCs both cell intrinsically and extrinsically, but it is unknown in which cell type and how BMI1 functions to maintain HSCs extrinsically. Here we show that Bmi1 maintains HSCs by preventing adipogenic differentiation of BMSCs. Bmi1 is highly expressed in BMSCs but becomes downregulated upon adipogenic differentiation and during aging. Deleting Bmi1 from BMSCs increased marrow adipocytes, induced HSC quiescence and depletion, and impaired hematopoiesis. We found that BMI1 repressed multiple developmental programs in BMSCs by safeguarding the repressive epigenetic marks histone H2A ubiquitylation and H3 lysine 27 trimethylation. We identified a novel adipogenic program governed by Pax3, which BMI1 repressed in BMSCs. Our results establish Bmi1 as a critical regulator of BMSC cell fate that suppresses marrow adipogenesis to create a supportive niche for HSCs. [Display omitted] •Bmi1 prevents adipogenesis and promotes osteogenesis by bone marrow stromal cells•Adipocyte expansion after Bmi1 loss in stroma depletes hematopoietic stem cells•Loss of Bmi1 reduces repressive histone marks on target genes Ink4a/Arf and Pax3•Derepressed Pax3 after Bmi1 ablation promotes adipocytic differentiation Nakada and colleagues show that Bmi1 is highly expressed in bone marrow stromal cells, loss of which caused marrow adipocyte expansion and hematopoietic stem cell depletion. Bmi1 deletion diminished repressive histone marks on Pax3, leading to its expression and adipogenesis. Reduced Bmi1 expression with age may contribute to age-associated increase of marrow adipocytes.