FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging
Open accessAbstract
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.
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Ageing and genotoxic stress induce cellular senescence of haematopoietic stem cells and osteoprogenitor cells, with subsequent decline in their functions in both mice and humans.
“Ageing and genotoxic stress induce cellular senescence of these stem cells 96,97 and osteoprogenitor cells, 98,99 with subsequent decline in the functions of these cells in both mice and humans.100”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [98]
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Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1
Wu, M., Tang, W., Chen, Y., Xue, L., Dai, J. Y., Li, Y., Zhu, X., Wu, C., Xiong, J., Zhang, J., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00607-1 · Cited by 151 · see citing works
The costs and benefits of senotherapeutics for human health
Raffaele, M., & Vinciguerra, M. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00300-7 · Cited by 140 · see citing works
Mi, B.-B., Xiong, Y., Knoedler, S. A., Alfertshofer, M. G., Panayi, A. C., Wang, H., Lin, S.-E., Li, G., & Liu, G. (2024) · Bone Research · doi:10.1038/s41413-024-00346-4 · Cited by 138 · see citing works
“1 cells, observed in conditions like COVID-19.”
BackgroundMolecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging
Neri, S., & Borzı̀, R. M. (2020) · Biomolecules · doi:10.3390/biom10020340 · Cited by 122 · see citing works
“It also downregulated polycomb proteins and upregulated miRNAs targeting polycomb proteins expression levels [79,80].”
BackgroundAli, D., Tencerova, M., Figeac, F., Kassem, M., & Jafari, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.981487 · Cited by 122 · see citing works
“Mouse genetic studies had shown that conditional depletion of Foxp1 in BMSCs leads to premature aging, bone loss, and increased BMA via Foxp1 interactions with different members of C/EBP family proteins, such as C/EBP b/d, which are key modulators of adipogenesis (38).”
BackgroundThe Long Non-coding RNA-ORLNC1 Regulates Bone Mass by Directing Mesenchymal Stem Cell Fate
Yang, L., Li, Y., Gong, R., Gao, M., Feng, C., Liu, T., Sun, Y., Jin, M., Wang, D., Yuan, Y., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.11.019 · Cited by 117 · see citing works
“In certain inductive microenvironments, BMSCs can differentiate into a variety of cell types, such as osteoblasts, adipocytes, chondrocytes, neurons, myocytes, myoblasts, etc.(8) Such a property makes BMSCs an attractive candidate for cell therapy and tissue engineering.”
BackgroundAdult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6
Zhang, Y., Guo, L., Han, S., Chen, L., Li, C., Zhang, Z., Hong, Y., Zhang, X., Zhou, X., Jiang, D., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03289-w · Cited by 112 · see citing works
Corrado, A., Cici, D., Rotondo, C., Maruotti, N., & Cantatore, F. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103679 · Cited by 101 · see citing works
“In a murine model of accelerated senescence, the increase in ROS and the reduced BMD observed with age were associated with an increased expression of FoxO target genes as a defense mechanism and with a concomitant decreased expression of β-catenin/T-cell factor (TCF)-related genes.”
BackgroundInfluentialLiu, W., Zhang, L., Xuan, K., Hu, C., Liu, S., Liao, L., Li, B., Jin, F., Shi, S., & Jin, Y. J. (2018) · Bone Research · doi:10.1038/s41413-018-0029-4 · Cited by 98 · see citing works
Osteocytes regulate senescence of bone and bone marrow
Ding, P., Gao, C., Gao, Y., Liu, D., Li, H., Xu, J., Chen, X., Huang, Y., Zhang, C., Zheng, M., et al. (2022) · eLife · doi:10.7554/elife.81480 · Cited by 102 · see citing works
“Senescent 387 osteoprogenitors have reduced self-renewal capacity and predominantly differentiate 388 into adipocytes as opposed to osteoblasts (Chen, et al. 2016; Li et al. 2017; Rosen et 389 al.”
H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells
Wang, L., Niu, N., Li, L., Shao, R., Ouyang, H., & Zou, W. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2006522 · Cited by 92 · see citing works
Epigenetic regulations of cellular senescence in osteoporosis
Huo, S., Tang, X., Chen, W., Gan, D., Guo, H., Yao, Q., Liao, R., Huang, T., Wu, J., Yang, J., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102235 · Cited by 87 · see citing works
Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis
Dai, B., Xu, J., Li, X., Huang, L., Hopkins, C., Wang, H., Yao, H., Mi, J., Zheng, L., Wang, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27683-w · Cited by 89 · see citing works
Wei, X., Li, S., He, J., Du, H., Liu, Y., Yu, W., Hu, H., Han, L., Wang, C., Li, H., et al. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0373-z · Cited by 84 · see citing works
Splicing factor YBX1 regulates bone marrow stromal cell fate during aging
Xiao, Y., Cai, G., Xu, F., Li, Y., Guo, W., Guo, Q., Huang, Y., Su, T., Li, C., Luo, X., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022111762 · Cited by 77 · see citing works
The implications of bone marrow adipose tissue on inflammaging
Aaron, N., Costa, S., Rosen, C. J., & Qiang, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.853765 · Cited by 74 · see citing works
Liu, P., Huang, S., Ling, S., Xu, S., Wang, F., Zhang, W., Zhou, R., He, L., Xia, X., Yao, Z., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12988-8 · Cited by 76 · see citing works
Biology of Tendon Stem Cells and Tendon in Aging
Lui, P. P. Y., & Wong, C. M. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2019.01338 · Cited by 76 · see citing works
“It controlled MSC fate and senescence during skeletal aging (Li et al., 2017).”
BackgroundMechanistic advances in osteoporosis and anti‐osteoporosis therapies
Wang, H., Luo, Y., Wang, H., Li, F., Yu, F., & Ye, L. (2023) · MedComm · doi:10.1002/mco2.244 · Cited by 76 · see citing works
Li, T., Su, X., Lu, P., Kang, X., Hu, M., Li, C., Wang, S., Lu, D., Shen, S., Huang, H., et al. (2023) · Advanced Science · doi:10.1002/advs.202206432 · Cited by 74 · see citing works
Aging and lineage allocation changes of bone marrow skeletal (stromal) stem cells
Nehlin, J. O., Jafari, A., Tencerová, M., & Kassem, M. S. (2019) · Bone · doi:10.1016/j.bone.2019.03.041 · Cited by 68 · see citing works
“FOXP1 influenced adipose cell-fate through interactions with the C/EBPβ/δ key modulators of adipogenesis and directly repressed transcription of p16INK4A (47) (47).”
BackgroundHao, X., Shen, Y., Chen, N., Zhang, W., Valverde, E., Wu, L., Chan, H. L., Xu, Z., Yu, L., Gao, Y., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.04.005 · Cited by 69 · see citing works
Members of FOX family could be drug targets of cancers
Wang, J., Li, W., Zhao, Y., Kang, D., Fu, W., Zheng, X., Pang, X., & Du, G. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.08.003 · Cited by 66 · see citing works
The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis
Wu, J., Zhang, W., Ran, Q., Xiang, Y., Zhong, J. F., Li, S. C., & Li, Z. (2018) · Stem Cells International · doi:10.1155/2018/1540148 · Cited by 66 · see citing works
“Cellular senescence results in the decline of FOXP1 [84] and an increase in miR-188 [88], which correlate with reduced osteogenic differentiation and increased adipogenic differentiation.”
Stem Cell-Laden Hydrogel-Based 3D Bioprinting for Bone and Cartilage Tissue Engineering
Yang, Z., Yi, P., Liu, Z., Zhang, W., Mei, L., Feng, C., Tu, C., & Li, Z. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.865770 · Cited by 67 · see citing works
From Stem Cells to Bone-Forming Cells
Donsante, S., Palmisano, B., Serafini, M., Robey, P. G., Corsi, A., & Riminucci, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083989 · Cited by 63 · see citing works
“, oxidative stress [146], have been demonstrated to occur in BMSCs/SSCs both in vivo and in vitro [88,145], with consequent negative impact on their differentiation capacity and on their ability to regenerate bone.”
BackgroundInfluentialShen, W. X., Sun, B., Zhou, C., Ming, W., Zhang, S., & Wu, X. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15792 · Cited by 62 · see citing works
The Mechanotransduction Signaling Pathways in the Regulation of Osteogenesis
Liu, Z., Wang, Q., Zhang, J., Qi, S., Duan, Y., & Li, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814326 · Cited by 63 · see citing works
“TF Forkhead box P1 (FOXP1) stimulates both the osteogenic di ff erentiation of MSCs and the osteoblast mineralization [53,54].”
The Role of Adipose Stem Cells in Bone Regeneration and Bone Tissue Engineering
Mende, W., Götzl, R., Kubo, Y., Pufe, T., Ruhl, T., & Beier, J. P. (2021) · Cells · doi:10.3390/cells10050975 · Cited by 60 · see citing works
“Studies have shown that several osteogenic transcription factors are reduced in older MSCs, including MAF bZIP transcription factor [28], Forkhead box P1 [29], and Core-binding factor β [30].”
BackgroundBone Marrow Adipocytes: A Critical Player in the Bone Marrow Microenvironment
Wang, L., Zhang, H., Wang, S., Chen, X., & Su, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.770705 · Cited by 55 · see citing works
“Forkhead box P1 (FOXP1) can interact with the CEBPβ/δ complex and RBPjκ to regulate BMSC fate switches (Li et al., 2017).”
BackgroundCai, G., Liu, Y., Luo, L., Xiao, Y., Jiang, T.-J., Yuan, J., & Wang, M. (2022) · Cell Proliferation · doi:10.1111/cpr.13178 · Cited by 55 · see citing works
Fibroblasts as Turned Agents in Cancer Progression
Wieder, R. (2023) · Cancers · doi:10.3390/cancers15072014 · Cited by 54 · see citing works
Suo, J., Zou, S., Wang, J., Han, Y., Zhang, L., Lv, C., Jiang, B., Ren, Q., Chen, L., Yang, L., et al. (2022) · Bone Research · doi:10.1038/s41413-022-00202-3 · Cited by 52 · see citing works
“Existing studies on osteoporosis have mainly focused on transcription factors, epigenetics and hormone metabolism.(4,36,37) However, the mechanism of RNA-binding proteins involved in regulating osteoporosis remains to be discovered.”
BackgroundTargeting Cell Senescence for the Treatment of Age-Related Bone Loss
Pignolo, R. J., Samsonraj, R. M., Law, S. F., Wang, H., & Chandra, A. (2019) · Current Osteoporosis Reports · doi:10.1007/s11914-019-00504-2 · Cited by 51 · see citing works
Aging, obese-insulin resistance, and bone remodeling
Imerb, N., Thonusin, C., Chattipakorn, N., & Chattipakorn, S. C. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111335 · Cited by 51 · see citing works
Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging
Peng, X., Zhou, X. H., Yin, Y., Luo, B., Liu, Y., & Yang, C. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.870324 · Cited by 50 · see citing works
“It is well known that the lineage of the bone marrow cells changes with age and is characterized by an obvious reduction in osteogenesis and an increase in adipogenesis (Li et al., 2017; Infante and Rodríguez, 2018).”
BackgroundFOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53
Li, H., Han, X., Yang, S., Wang, Y., Dong, Y., & Tang, T. (2021) · Oncogene · doi:10.1038/s41388-021-01742-4 · Cited by 49 · see citing works
Zhang, L., Guan, Q., Wang, Z., Feng, J., Zou, J., & Gao, B. (2023) · Aging and Disease · doi:10.14336/ad.2023.1115 · Cited by 55 · see citing works
“The expression of forkhead box protein 1 (FOXP1) [21], discoid domain receptor 2 (DDR2) [22], osteoprotegerin (OPG) [18, 19], osteoblast-specific transcription factor Runt-related transcription factor 2 (Runx2), distal-less homeobox 5 (Dlx5), the osteoblast marker collagen [20], peroxisome…”
Cellular senescence and hematological malignancies: From pathogenesis to therapeutics
Hu, D., Yuan, S., Zhong, J., Liu, Z., Wang, Y., Liu, L., Li, J., Wen, F., Liu, J., & Zhang, J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107817 · Cited by 45 · see citing works
BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism
Du, J., Liu, Y., Wu, X., Sun, J., Shi, J., Zhang, H., Ao, Z., Zhou, M., & Jiang, X. (2023) · Nature Communications · doi:10.1038/s41467-023-37116-5 · Cited by 45 · see citing works
Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion
Xu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1721820115 · Cited by 44 · see citing works
“Our previous study demonstrated that Foxp1 promotes MSC osteogenic differentiation by repressing Notch signaling (36).”
Liu, W., Zhang, L., Xuan, K., Hu, C., Li, L., Zhang, Y., Jin, F., & Jin, Y. J. (2018) · Theranostics · doi:10.7150/thno.27372 · Cited by 44 · see citing works
“Currently, the regulators of lineage reciprocity of BMMSCs have all been identified as transcription factors [7-9], and researchers have not determined whether other genes control the lineage differentiation of BMMSCs.”
BackgroundXu, L., Wang, Y., Wang, J., Zhai, J., Ren, L., & Zhu, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179323 · Cited by 42 · see citing works
Cellular senescence in tissue repair: every cloud has a silver lining
Yun, M. H. (2018) · The International Journal of Developmental Biology · doi:10.1387/ijdb.180081my · Cited by 42 · see citing works
“In the latter, it has recently been shown that the levels of the transcription factor FoxP1 decline during Ageing, leading to increases in p16 expression and MSC senescence.”
BackgroundCheng, K., Chen, I.-C., Cheng, C.-H., Mutoji, K., Hale, B., Hermann, B. P., Geyer, C. B., Oatley, J., & McCarrey, J. (2019) · bioRxiv · doi:10.1016/j.isci.2020.101596 · Cited by 31 · see citing works
GATA6 regulates aging of human mesenchymal stem/stromal cells
Jiao, H., Walczak, B. E., Lee, M., Lemieux, M. E., & Li, W. (2020) · Stem Cells · doi:10.1002/stem.3297 · Cited by 38 · see citing works
“It has been reported that forkhead box P1 (FOXP1), another TF of the FOX family, plays a critical role in controlling fate commitment and senescence of mesenchymal stem cells (MSCs) during skeletal aging.(14) Nuclear factor-kappa B and paired box gene 5 have also been shown involved in the regulation of keratinocyte s…”
BackgroundAn, F., Wang, X., Wang, C., Liu, Y., Sun, B., Zhang, J., Gao, P., & Yan, C. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1210627 · Cited by 41 · see citing works
“However, during aging, or other pathological stimuli, BMSCs preferentially differentiate into adipocytes, resulting in an increase in bone marrow adipocytes and a decrease in osteoblasts and bone formation (14, 15).”
BackgroundYuan, K., Yang, Y., Lin, Y., Zhou, F., Huang, K., Yang, S., Kong, W., Li, F., Kan, T., Wang, Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202404453 · Cited by 38 · see citing works
Ye, C., Chen, M., Chen, E., Li, W., Wang, S., Ding, Q., Wang, C., Zhou, C., Tang, L. F., Hou, W., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0857-6 · Cited by 38 · see citing works
Mei, J., Zhou, F. L., Qiao, H., Li, H., & Tang, T. (2019) · Theranostics · doi:10.7150/thno.33908 · Cited by 38 · see citing works
“We performed western blotting as previously described [33], and the relative intensities of bands”
MethodBone metabolism regulation: Implications for the treatment of bone diseases
Yao, D., Huang, L., Ke, J., Zhang, M., Xiao, Q., & Zhu, X. M. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110494 · Cited by 38 · see citing works
Neyroud, D., Nosacka, R. L., Callaway, C. S., Trevino, J. G., Hu, H., Judge, S. M., & Judge, A. R. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12666 · Cited by 35 · see citing works
CGRP Regulates the Age-Related Switch Between Osteoblast and Adipocyte Differentiation
Li, H., Qu, J., Zhu, H., Wang, J., He, H., Xie, X., Wu, R., & Lu, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.675503 · Cited by 37 · see citing works
Luo, Z., Wei, W., Qiu, D., Su, Z., Liu, L., Zhou, H., Cui, H., & Yang, L. (2024) · Bone Research · doi:10.1038/s41413-024-00351-7 · Cited by 35 · see citing works
“13 For example, modi fi cation of transcription factors, 6,7 epigenetics 10 – 14 and autophagy 5,15,16 that enhanced osteogenesis and decreased adipogenesis of BMSCs alleviated SOP in mice.”
BackgroundBai, M., Han, Y., Wu, Y., Liao, J., Li, L., Wang, L., Li, Q., Xing, W., Chen, L., Zou, W., et al. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000350 · Cited by 32 · see citing works
Liao, Z., Yu, J. H., Chu, Y., Wu, H., Li, X., Deng, Z., Feng, S., Chen, N., Luo, Z., Zheng, X., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03271-6 · Cited by 32 · see citing works
Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging
Cheng, M., Yuan, W., Moshaverinia, A., & Yu, B. (2023) · Cells · doi:10.3390/cells12070998 · Cited by 33 · see citing works
“The main characteristics of senescent BM-MSCs include halted proliferation, reduced self-renewal and impaired differentiation, leading to “stem cell exhaustion” in vivo [28] and contributing to the impaired bone mass and delayed repair in long-bone [29,30].”
BackgroundLoss of Notch signaling in skeletal stem cells enhances bone formation with aging
Remark, L. H., Leclerc, K., Ramsukh, M., Lin, Z., Lee, S., Dharmalingam, B., Gillinov, L. A., Nayak, V. V., Parente, P. E., Sambon, M., et al. (2023) · Bone Research · doi:10.1038/s41413-023-00283-8 · Cited by 31 · see citing works
Mesenchymal stem cells and dental implant osseointegration during aging: from mechanisms to therapy
Ma, Y., Wang, S., Wang, H., Chen, X., Shuai, Y., Wang, H., Mao, Y., & He, F. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03611-1 · Cited by 34 · see citing works
“…have shown that the expression of transcription factors, including FOXP1, MAF, CBFβ, and SATB2, could potentially affect and attenuate senescence-related changes, including reduced bone mineral density, decreased trabecular thickness, and increased bone marrow adipogenic differentiation [55–58].”
BackgroundSenescent mesenchymal stem/stromal cells and restoring their cellular functions
Meng, Q., Liu, J., Lü, W., Fan, H., Zhou, X., & Liang, X. (2020) · World Journal of Stem Cells · doi:10.4252/wjsc.v12.i9.966 · Cited by 32 · see citing works
Chen, P., Hu, B., Xie, L., Jiang, T., Xia, Z., & Peng, H. (2021) · Cell Proliferation · doi:10.1111/cpr.13095 · Cited by 32 · see citing works
Li, H., Liang, J., Feng, Q. F., & Zhai, Y. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.09.161 · Cited by 30 · see citing works
Mesenchymal stem cells: ideal seeds for treating diseases
Gao, G., Fan, C., Li, J. W., Liang, R., Wei, C., Chen, X., Yang, Y., Zhong, Y., Shao, Y., Kong, Y., et al. (2021) · Human Cell · doi:10.1007/s13577-021-00578-0 · Cited by 29 · see citing works
FGFR2 accommodates osteogenic cell fate determination in human mesenchymal stem cells
Zhang, Y., Ling, L., Ajayakumar, A. A. D. O., Eio, M. Y., van Wijnen, A. J., Nurcombe, V., & Cool, S. M. (2022) · Gene · doi:10.1016/j.gene.2022.146199 · Cited by 30 · see citing works
Qiao, H., Mei, J., Yuan, K., Zhang, K., Zhou, F., Tang, T., & Zhao, J. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01536-0 · Cited by 30 · see citing works
“The supernatant was centrifuged at 4 °C for 20 min at 12,000 rpm, and a small amount of the supernatant was taken for western blot analysis as previously reported [74, 75].”
MethodLoss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging
Deng, P., Chang, I., Wang, J., Badreldin, A. A., Li, X., Yu, B., & Wang, C. (2022) · International Journal of Oral Science · doi:10.1038/s41368-022-00175-3 · Cited by 29 · see citing works
Massaro, F., Corrillon, F., Stamatopoulos, B., Meuleman, N., Lagneaux, L., & Bron, D. (2020) · Cancers · doi:10.3390/cancers13010068 · Cited by 28 · see citing works
“In mice, it has been shown that FOXP1, a transcription factor interacting with CEBPβ, is downregulated during aging [87].”
BackgroundAged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies
Yang, X. F., Wang, Y., Rovella, V., Candi, E., Jia, W. P., Bernassola, F., Bove, P., Piacentini, M., Scimeca, M., Sica, G. S., et al. (2023) · Biology Direct · doi:10.1186/s13062-023-00394-6 · Cited by 27 · see citing works
Li, B., Wang, J., Xu, F., Wang, Q., Liu, Q., Wang, G., Miao, D., & Sun, Q. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10408-x · Cited by 26 · see citing works
Li, Y., Hu, M., Xie, J., Li, S., & Dai, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03393-6 · Cited by 26 · see citing works
“Skeletal ageing is a progressive process that involves the inevitable exhaustion and senescence of BM-MSCs and a subsequent decline in bone homeostasis, accompanied by an elevated propensity for increased bone marrow adipose tissue (BMAT) and decreased bone mass [2, 12].”
BackgroundBone marrow adipocytes: key players in vascular niches, aging, and disease
Fan, Y., El-Khalek, M. K. A., Zhang, Y., Liu, L., Tian, Q., Chueakula, N., Ramasamy, S. K., Dalan, R., Habib, S. J., & Kusumbe, A. P. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1633801 · Cited by 26 · see citing works
“The transcription factor FOXP1, which normally interacts with C/EBPβ/δ and Notch signaling to promote osteogenesis and restrain adipogenesis, is reduced with aging (Li et al., 2017).”
InfluentialТодосенко, Н. М., Хазиахматова, О. Г., Malashchenko, V. V., Yurova, K. A., Bograya, M., Beletskaya, M., Vulf, M. A., Mikhailova, L. V., Minchenko, A., Soroko, I., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512259 · Cited by 26 · see citing works
“In mouse models, FOXP1—a regulator of the pro-adipogenic CEBPβ/δ complex in BMAs–has been shown to attenuate aging by downregulating p16 INK4A (encoded by CDKN2A), a cell-cycle repressor that induces G1 phase arrest [76].”
BackgroundAwakening of Dormant Breast Cancer Cells in the Bone Marrow
Wieder, R. (2023) · Cancers · doi:10.3390/cancers15113021 · Cited by 24 · see citing works
The role of GATA4 in mesenchymal stem cell senescence: A new frontier in regenerative medicine
Babu, M. A., Renuka Jyothi, S., Kaur, I., Kumar, S., Sharma, N., Kumar, M., Rajput, P., Ali, H., Gupta, G., Subramaniyan, V., et al. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.11.017 · Cited by 24 · see citing works
“Finally, overexpression of the FOXp1 effectuating vector was capable of immortalizing mesenchymal stem cells [87].”
Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis
Chen, F., Wang, S., Zeng, C., Tang, S., Gu, H., Wang, Z., Li, J., Feng, P., Zhang, Y., Wang, P., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04975-6 · Cited by 24 · see citing works
“Cellular senescence”
Li, J., Lu, L., Liu, Y., & Yu, X. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02164-1 · Cited by 23 · see citing works
“Accordingly, declined FOXP1 in BMSCs from aged mice results in enlarged bone marrow adiposity and reduced bone mass [24].”
Liu, P., An, Y., Zhu, T., Tang, S., Huang, X., Li, S., Fu, F., Ji, C., & Xuan, K. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1131218 · Cited by 25 · see citing works
“It has been well documented that BMMSCs suffer from reduced proliferation with a differentiation shift from osteogenesis to adipogenesis in osteopenias of diverse pathologies (Liu et al., 2016; Sui et al., 2016a; Li et al., 2017).”
BackgroundRegulation of osteogenesis via miR-101-3p in mesenchymal stem cells by human gingival fibroblasts
Kaneda‐Ikeda, E., Iwata, T., Mizuno, N., Nagahara, T., Kajiya, M., Ouhara, K., Yoshioka, M., Ishida, S., Kawaguchi, H., & Kurihara, H. (2020) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-019-01080-2 · Cited by 23 · see citing works
“Moreover, FOXP1 controls MSC neural differentiation, commitment, and senescence [31, 32].”
BackgroundXu, Y., Chang, L., Chen, Y., Zhou, D., Zhou, L., Tang, J., Deng, L., Tang, G., & Li, C. (2024) · Advanced Science · doi:10.1002/advs.202406428 · Cited by 21 · see citing works
The Role of Forkhead Box Family in Bone Metabolism and Diseases
Xu, J., Wang, K., Zhang, Z., Xue, D., Li, W., & Pan, Z. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.772237 · Cited by 22 · see citing works
“found that FoxP1 favors bone formation over adipogenesis and may be a potential target gene for the treatment of osteoporosis (Li et al., 2017).”
BackgroundApplying causal discovery to single-cell analyses using CausalCell
Wen, Y., Huang, J., Zhang, H., Guo, S., Elyahu, Y., Monsonego, A., Ding, Y., & Zhu, H. (2023) · eLife · doi:10.7554/elife.81464 · Cited by 23 · see citing works
Downregulation of FOXP1 correlates with tendon stem/progenitor cells aging
Xu, H., & Liu, F. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.08.136 · Cited by 22 · see citing works
Tian, R.-C., Zhang, R., & Ma, C. (2025) · Biomolecules · doi:10.3390/biom15020276 · Cited by 21 · see citing works
“Conversely, the adipogenic potential of elderly BM-MSCs is increased [24].”
Li, J., Xie, R., Jiang, F., Li, Y., Zhu, Y. P., Liu, Z., Liao, M., Liu, Y., Meng, X., Chen, S., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202100807rr · Cited by 20 · see citing works
Wang, T., Yang, L., Liang, Z., Bai, L., Pei, H., Zhang, T., Wu, L., Wang, L., Wang, X., You, X., et al. (2021) · Biomaterials Advances · doi:10.1016/j.msec.2021.112635 · Cited by 20 · see citing works
Wang, J., Xin, Y., Dong, Z., Li, S., & Yang, G. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112974 · Cited by 21 · see citing works
Differential regulation of skeletal stem/progenitor cells in distinct skeletal compartments
Solidum, J., Jeong, Y., Heralde, F., & Park, D. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1137063 · Cited by 17 · see citing works
“Forkhead box P1 (FOXP1) also declines with age, losing its anti-adipocyte interaction with C/EBPβ and proosteogenic repression of Notch signaling pathway, all leading to bone loss (Li et al., 2017).”
Background
- Authors
- Li, H., Liu, P., Xu, S., Li, Y., Dekker, J. D., Li, B., Fan, Y., Zhang, Z., Hong, Y., Yang, G., Tang, T., Ren, Y., Tucker, H. O., Yao, Z., & Guo, X.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- The University of Texas at Austin (US)
- Shanghai Sixth People's Hospital (CN)
- Nanjing First Hospital (CN)
- Corresponding author
- Guo, Xizhi
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2017-02-27
- Volume
- 127
- Issue
- 4
- Pages
- 1241-1253
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5373872
- OpenAlex
- W2591050028
- Cited by
- 180
- References
- 74
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 24 · 2023: 33 · 2022: 27 · 2021: 18 · 2020: 18 · 2019: 9 · 2018: 18 · 2017: 3
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Lymphoma Research Foundation (300463)
- Cancer Prevention and Research Institute of Texas (RP120459, RP120348 and RP120459, RP120348)
- National Natural Science Foundation of China (973 Program, 31171396, 31100624, 2012CB966903, 31271553, 81421061, 81200586, 2014CB942902, R01CA31534)
- National Institutes of Health (31100624, 31271553, 2014CB942902, 31171396, 81421061, 2012CB966903)
- National Key Research and Development Program of China (31271553, 2012CB966903, R01CA31534, 31100624, 31171396, 2014CB942902, 81421061)
- National Cancer Institute (R01CA031534)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- FOXP1, mesenchymal stem cells, skeletal aging, cellular senescence, p16INK4a, bone marrow adiposity, bone formation, adipogenesis, lineage commitment, transcriptional repression, replicative capacity, bone mass
- MeSH terms
- Animals, Bone Marrow Cells, Cell Line, Humans, Osteogenesis, Repressor Proteins, Cellular Senescence, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, CCAAT-Enhancer-Binding Protein-beta, Adipogenesis, Mice, CCAAT-Enhancer-Binding Protein-delta, Forkhead Transcription Factors, Mesenchymal Stem Cells
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