FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging
Hanjun Li, … , Zhengju Yao, Xizhi Guo
Hanjun Li, … , Zhengju Yao, Xizhi Guo
Published April 3, 2017; First 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 Stem cells

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

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 1

Foxp1 expression declines with age in BM MSCs.

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Foxp1 expression declines with age in BM MSCs. (A) Representative image...
(A) Representative image of IHC analysis. IHC showed overlapping of FOXP1 (green) and nestin (red) in fibroblast-like cells adjacent to endosteal (white arrows) in neonatal BM. Scale bar: 100 μm. (B) Western blotting for the FOXP1 protein levels in BM MSCs. Western blotting for BM MSCs at 1, 8, and 30 months detected 3 major isoforms: FOXP1A (95 kD), FOXP1D (70 kD), and FOXP1C (50 kD). n = 3. (C) qPCR for the relative expression of Foxp1 isoforms AB, ABD, ACD, and ABCD in MPCs from BM of 1 and 8 months old. n = 3. (D) Relative expression levels of FOXP1 in young and aged hMPC as detected by qPCR. (E) Western blotting for FOXP1 protein levels in human BM MSCs from donors ages 26, 27, 33, 41, 74, 75 and 82 years. (F) Inverse expressions of Foxp1 and p16INK4A (p16) were assessed by qPCR in primitive MSCs obtained from BM of 1-, 8-, and 30-month-old mice. (G) Inverse correlation of Foxp1 and p16INK4A expression levels during in vitro expansion and passaging (P1–P6) of murine MSCs. n = 3. (H) Methylation of CpG islands within the Foxp1 promoter variant 3 (–196 to 1) as detected by bisulfite sequencing in 1- and 12-month-old MSCs. Black circles represent methylated CpG islands and white circles unmethylated CpG islands. n = 3. *P < 0.05; **P < 0.01.