Bmi1 Suppresses Adipogenesis in the Hematopoietic Stem Cell Niche
Bmi1 Suppresses Adipogenesis in the Hematopoietic Stem Cell Niche
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DOI：
10.1016/j.stemcr.2019.05.027
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发表时间：
2019-09-10
影响因子：
5.9
通讯作者：
Nakada, Daisuke
中科院分区：
文献类型：
--
作者：
Hu, Tianyuan;Kitano, Ayumi;Nakada, Daisuke
表达高水平干细胞因子（SCF）和CXC趋化因子配体12（CXCL 12）的骨髓基质细胞（BMSC）是造血干细胞（HSC）生态位的重要组成部分。虽然BMSC产生的支持HSC的分泌因子已得到很好的描述，但关于控制BMSC细胞命运从而间接维持HSC的转录调节因子知之甚少。BMI1是一种多梳状结构蛋白，对HSC的细胞内和细胞外都有调节作用，但BMI1在哪种细胞类型中以及如何维持HSC的细胞外功能尚不清楚。在这里，我们表明Bmil通过阻止BMSCs的成脂分化来维持HSC。Bmil在BMSC中高度表达，但在成脂分化和衰老过程中下调。从BMSC中删除Bmi1增加骨髓脂肪细胞，诱导HSC静止和耗竭，并损害造血。我们发现BMI1通过保护抑制性表观遗传标记组蛋白H2A泛素化和H3赖氨酸27三甲基化来抑制BMSCs的多种发育程序。我们确定了一个新的脂肪形成程序由Pax3，BMI1抑制BMSCs。我们的研究结果证实Bmil是BMSC细胞命运的关键调节因子，它抑制骨髓脂肪生成，为HSC创造支持性生态位。
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 Bmil maintains HSCs by preventing adipogenic differentiation of BMSCs. Bmil 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 Bmil as a critical regulator of BMSC cell fate that suppresses marrow adipogenesis to create a supportive niche for HSCs.