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FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging
Hanjun Li, … , Zhengju Yao, Xizhi Guo
Hanjun Li, … , Zhengju Yao, Xizhi Guo
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1241-1253. https://doi.org/10.1172/JCI89511.
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Research Article Aging Article has an altmetric score of 6

FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging

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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

Hanjun Li, Pei Liu, Shuqin Xu, Yinghua Li, Joseph D. Dekker, Baojie Li, Ying Fan, Zhenlin Zhang, Yang Hong, Gong Yang, Tingting Tang, Yongxin Ren, Haley O. Tucker, Zhengju Yao, Xizhi Guo

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Figure 4

FOXP1 controls adipocyte and osteoblast differentiation by interacting with CEBPβ/δ and RBPjκ.

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FOXP1 controls adipocyte and osteoblast differentiation by interacting w...
(A and B) In vitro co-IP of FOXP1-His with CEBPβ-Flag (A) or CEBPδ-Flag (B) following transfection into 3T3-L1 cells. (C) Western blotting detection of CEBPβ and CEBPδ in FOXP1 immunoprecipitates from primary BM MSCs. (D) Colocalization of FOXP1 and CEBPβ, CEBPδ or RBPjκ in the nuclei of C3H10T1/2 cells transfected with FOXP1-His and CEBPβ/δ- or RBPjκ-expressing vectors. Green, anti-His antibody; red, antibodies for CEBPβ, CEBPδ, or RBPjκ; blue, DAPI staining for nucleus. Scale bar: 50 μm. (E) FOXP1 represses the transactivation ability of CEBPβ and CEBPδ in inducing Pparg-Luc luciferase activity in C3H10T1/2 cells. n = 3. (F) Western blot detection of PPARγ and FABP4 levels in Foxp1Prx1Δ/Δ mutant BM at 8 months. (G) qRT-PCR of Pparg mRNA levels in MSCs. n = 3. (H and I) Promoter occupancy of Pparg gene as assessed by anti-FOXP1 ChIP-PCR in MSCs. (J and K) Co-IP of FOXP1 with RBPjκ in C3H10T1/2 cells (J) and BM MSCs (K). (L) FOXP1 repression of luciferase activity as judged by Rbpjk-Luc reporter activity following the induction by NICD in C3H10T1/2 cells. n = 3. (M and N) qPCR confirms relatively higher expression levels of Hey1 and Heyl in MSCs from Foxp1Prx1Δ/Δ mutant BM (M) or C3H10T1/2 cells transfected with pMSCV-FOXP1 (N). n = 3. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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