A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBP&bgr;/&dgr; complex and recombination signal binding protein for immunoglobulin &kgr; J region (RBPj&kgr;), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.

中文翻译：

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FOXP1在骨骼衰老过程中控制间充质干细胞的定型和衰老

骨髓中老化的间充质干/祖细胞（MSC）的标志是从成骨细胞到脂肪细胞分化能力的关键，以及自我更新能力的降低。然而，这些细胞事件在衰老过程中是如何被组织的还没有被完全理解。在这项研究中，我们已经使用分子和遗传方法来研究叉头盒P1（FOXP1）在MSC衰老的转录控制中的作用。在骨髓MSC中，FOXP1表达水平随年龄的增长而下降，与衰老标记p16INK4A的表达相反。骨髓MSCs中Foxp1的条件耗竭导致过早的衰老特征，包括增加的小鼠肥胖，降低的骨量和受损的MSC自我更新能力。在分子水平上 FOXP1通过与CEBP相互作用来调节MSC的细胞命运选择。免疫球蛋白的复合和重组信号结合蛋白 J区（RBPj＆kgr;），分别是脂肪形成和成骨的关键调节因子。Foxp1缺失的MSC中p16INK4A的缺失部分挽救了复制能力和应得的骨量缺陷。启动子占用分析表明，FOXP1直接抑制p16INK4A的转录。这些结果表明，FOXP1通过协调其细胞命运开关来减弱MSC衰老，同时以剂量和年龄依赖性的方式维持其复制能力。分别。Foxp1缺失的MSC中p16INK4A的缺失部分挽救了复制能力和应得的骨量缺陷。启动子占用分析表明，FOXP1直接抑制p16INK4A的转录。这些结果表明，FOXP1通过协调其细胞命运开关来减弱MSC衰老，同时以剂量和年龄依赖性的方式维持其复制能力。分别。Foxp1缺失的MSC中p16INK4A的缺失部分挽救了复制能力和应得的骨量缺陷。启动子占用分析表明，FOXP1直接抑制p16INK4A的转录。这些结果表明，FOXP1通过协调其细胞命运开关来减弱MSC衰老，同时以剂量和年龄依赖性的方式维持其复制能力。