Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of HSC functional decline and find strategies to counteract these, we established a model in which Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSCs from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the `ROS pathway´ and reduced single cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (beta-catenin) elevated, but so was its association with the phosphorylated coactivator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2APR72/130 by IQ-1 administration in OS1Δ/Δ mice. This treatment not only reduced Catenin beta-1/phospho-p300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of nuclear Catenin beta-1/phospho-p300 association is a new strategy to restore poor HSC function.

中文翻译：

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骨祖细胞 SFRP1 通过 PP2A-PR72/130 介导的 p300 调节防止造血干细胞耗尽。

慢性炎症和衰老过程中骨髓微环境的重塑会降低造血干细胞 (HSC) 的功能。为了评估 HSC 功能下降的机制并找到抵消这些机制的策略，我们建立了一个模型，其中 Sfrp1 基因在 Osterix+ 骨细胞（OS1Δ/Δ 小鼠）中被删除。来自这些小鼠的 HSCs 显示出与相关 DNA 损伤、“ROS 通路”的丰富表达和单细胞增殖减少相关的再生活性严重下降。有趣的是，不仅连环蛋白 beta-1（β-连环蛋白）的蛋白质水平升高，而且它与细胞核中磷酸化共激活因子 p300 的关联也升高。由于这两种蛋白质在促进分化和衰老中起着关键作用，我们通过在 OS1Δ/Δ 小鼠中施用 IQ-1 通过 PP2APR72/130 抑制了 p300 的体内磷酸化。这种治疗不仅减少了连环蛋白 beta-1/phospho-p300 关联，而且还减少了核 p300。更重要的是，体内 IQ-1 处理完全恢复了 OS1Δ/Δ 小鼠的 HSC 再生活性。我们的研究结果表明，骨祖细胞 Sfrp1 对于维持 HSC 功能至关重要。此外，核连环蛋白 beta-1/磷酸-p300 结合的药理下调是恢复不良 HSC 功能的新策略。