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 3

FOXP1 modulates cell-fate choice of MSCs between adipocytes and osteoblasts.

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FOXP1 modulates cell-fate choice of MSCs between adipocytes and osteobla...
(A) The osteogenic and adipogenic potential of MSCs from FOXP1 mutant BM was assessed 14 days after induction of differentiation by ALP and oil red O staining. n = 5. (B and C) Quantification of the frequencies of osteoblast clones (CFU-Ob) and adipocyte clones (CFU-Ad) following induction in A. n = 3. (D and E) Expression of bone (Alp, Col1a1) and fat (Pparg, Cebpa, and Fabp4) markers as assessed by quantitative reverse-transcriptase PCR (qRT-PCR) of uninduced MSCs in BM. n = 3. (F) Foxp1 was overexpressed in C3H10T1/2 cells by retrovirus (pMSCV-FOXP1) and cultured in differentiation medium. Cell differentiation was assessed 6 days after adipogenic induction by oil red O staining or 14 days after osteogenic induction by ALP staining. n = 3. Scale bar: 100μm (G) The expression of adipogenic markers (Cebpa, Pparg, and Fabp4) was analyzed 6 days after adipogenic induction of FOXP1-expressing C3H10T1/2 cells. n = 3. (H) The expression of bone markers (Runx2, Alp, Col1a1, and Osterix) was assessed by qPCR 14 days after osteogenic culture of FOXP1-overexpressing C3H10T1/2 cells. n = 3. *P < 0.05; ***P < 0.001.