title: FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging.
abstract: 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 CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), 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.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Li
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.forename: Shuqin
authors.initials: S
authors.lastname: Xu
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dekker
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
authors.forename: Gong
authors.initials: G
authors.lastname: Yang
authors.forename: Tingting
authors.initials: T
authors.lastname: Tang
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ren
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Yao
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C497252:CEBPD protein, human; C545013:Cebpb protein, mouse; C497253:Cebpd protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D012097:Repressor Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta