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.

An early‐senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro‐inflammatory program

“…The multipotent potential of MSC and their differentiation ability have been extensively dissected in mouse and human settings. In particular, several regulators of MSC biology including factors involved in bone formation have been shown to be dramatically reduced during aging, suggesting that aged MSC have a reduced differentiation capacity toward bone and are more primed to differentiate into the adipogenic lineage (Kim et al, ; Li et al, ; Ma et al, ). When testing the differentiation capacity of our aged human BM‐derived MSC, we did not detect any significant functional skewing of aged MSC toward adipocytes.…”

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

“…Bone marrow‐derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging (Wilson et al., 2010; Zhou et al., 2008). Different mechanisms of MSC senescence have been demonstrated including telomere shortening (Baxter et al., 2004), increased reactive oxygen species (ROS) (Stolzing & Scutt, 2006) and transcriptional control (Li et al., 2017). However, the complex molecular network is still largely unknown.…”

MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

“…[4][5][6][7] It has been reported, during ageing, BMSC have reduced ability of differentiating into osteoblasts but have increased ability of differentiating into adipocytes which causes age-related bone loss. [8][9][10] However, this mechanism still needs to further investigate. MicroRNAs (miRNAs), which means small non-coding RNAs, always act as an negative regulate factor over the process of expression of target genes by degrading mRNAs or inhibiting the translation of mRNAs.…”