Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Life Science, Faculty of Medicine, Shimane University, Izumo City, Shimane, Japan; PuREC Company, Ltd., Izumo City, Shimane, Japan.
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Exp Hematol. 2019 Aug;76:24-37. doi: 10.1016/j.exphem.2019.07.006. Epub 2019 Aug 11.
The polycomb group protein Bmi1 maintains hematopoietic stem cell (HSC) functions. We previously reported that Bmi1-deficient mice exhibited progressive fatty changes in bone marrow (BM). A large portion of HSCs reside in the perivascular niche created partly by endothelial cells and leptin receptor (LepR) BM stromal cells. To clarify how Bmi1 regulates the HSC niche, we specifically deleted Bmi1 in LepR cells in mice. The Bmi1 deletion promoted the adipogenic differentiation of LepR stromal cells and caused progressive fatty changes in the BM of limb bones with age, resulting in reductions in the numbers of HSCs and progenitors in BM and enhanced extramedullary hematopoiesis. This adipogenic change was also evident during BM regeneration after irradiation. Several adipogenic regulator genes appeared to be regulated by Bmi1. Our results indicate that Bmi1 keeps the adipogenic differentiation program repressed in BM stromal cells to maintain the integrity of the HSC niche.
多梳抑制复合物蛋白 Bmi1 维持造血干细胞 (HSC) 的功能。我们之前曾报道，Bmi1 缺陷小鼠的骨髓 (BM) 中出现进行性脂肪变化。大部分 HSCs 位于由内皮细胞和瘦素受体 (LepR) BM 基质细胞部分形成的血管周龛位中。为了阐明 Bmi1 如何调节 HSC 龛位，我们在小鼠中特异性地在 LepR 细胞中缺失了 Bmi1。Bmi1 的缺失促进了 LepR 基质细胞的成脂分化，并随着年龄的增长导致四肢骨 BM 中的脂肪变性逐渐加重，导致 BM 中 HSCs 和祖细胞数量减少，并增强了骨髓外造血。这种成脂变化在辐照后 BM 再生期间也很明显。一些成脂调节基因似乎受到 Bmi1 的调控。我们的结果表明，Bmi1 使 BM 基质细胞中的成脂分化程序受到抑制，以维持 HSC 龛位的完整性。
