Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 4, Pages 1241-1253Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI89511
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Funding
- National Major Fundamental Research 973 Program of China [2014CB942902, 2012CB966903]
- National Natural Science Foundation of China [31171396, 31271553, 81421061, 31100624, 81200586]
- NIH [R01CA31534]
- Cancer Prevention Research Institute of Texas [RP120348, RP120459]
- Marie Betzner Morrow Centennial Endowment
- Lymphoma Research Foundation [300463]
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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 p16(INK4A). 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 beta/delta complex and recombination signal binding protein for immunoglobulin. J region (RBPj kappa), 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.
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