MiR-1292 Targets FZD4 to Regulate Senescence and Osteogenic Differentiation of Stem Cells in TE/SJ/Mesenchymal Tissue System via the Wnt/β-catenin Pathway

With the expansion of the elderly population, age-related osteoporosis and the resulting bone loss have become a significant health and socioeconomic issue. In Triple Energizer (TE)/San Jiao (SJ)/mesenchymal tissue system, mesenchymal stem cell (MSC) senescence, and impaired osteogenesis are thought to contribute to age-related diseases such as osteoporosis. Therefore, comprehending the molecular mechanisms underlying MSC senescence and osteogenesis is essential to improve the treatment of bone metabolic diseases. With the increasing role of miRNAs in MSC aging and osteogenic differentiation, we need to understand further how miRNAs participate in relevant mechanisms. In this study, we observed that the expression of miR-1292 was augmented during cellular senescence and lessened with osteogenesis in human adipose-derived mesenchymal stem cells (hADSCs). miR-1292 expression was positively correlated with senescence markers and negatively associated with bone formation markers in clinical bone samples. Overexpression of miR-1292 notably accelerated hADSC senescence and restrained osteogenesis, whereas its knockdown decreased senescence and enhanced osteogenic differentiation. Furthermore, miR-1292 upregulation inhibited ectopic bone formation in vivo. Mechanistically, FZD4 was identified as a potential target of miR-1292. Downregulation of FZD4 phenocopied the effect of miR-1292 overexpression on hADSC senescence and osteogenic differentiation. Moreover, the impact of miR-1292 suppression on senescence and osteogenesis were reversed by the FZD4 knockdown. Pathway analysis revealed that miR-1292 regulates hADSC senescence and osteogenesis through the Wnt/β-catenin signaling pathway. Thus, TE/SJ/mesenchymal tissue system is the largest organ composed of various functional cells derived from mesoderm, responsible for maintaining homeostasis and regulating cell senescence. miR-1292 might serve as a novel therapeutic target for the prevention and treatment of osteoporosis or other diseases related to bone metabolism and aging.

[1]  Luchan Deng,et al.  MiRNA-10b Reciprocally Stimulates Osteogenesis and Inhibits Adipogenesis Partly through the TGF-β/SMAD2 Signaling Pathway , 2018, Aging and disease.

[2]  Hongling Li,et al.  Mesenchymal stem cells and immune disorders: from basic science to clinical transition , 2018, Frontiers of Medicine.

[3]  G. Barabino,et al.  Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro , 2018, Stem Cell Research & Therapy.

[4]  Neil D. Theise,et al.  Structure and Distribution of an Unrecognized Interstitium in Human Tissues , 2018, Scientific Reports.

[5]  K. Kang,et al.  miRNAs in stem cell aging and age-related disease , 2017, Mechanisms of Ageing and Development.

[6]  J. Davies,et al.  Concise Review: Musculoskeletal Stem Cells to Treat Age‐Related Osteoporosis , 2017, Stem cells translational medicine.

[7]  Shushan Zhao,et al.  miR-139-5p Represses BMSC Osteogenesis via Targeting Wnt/β-Catenin Signaling Pathway. , 2017, DNA and cell biology.

[8]  C. Henke,et al.  MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation , 2017, The Journal of Biological Chemistry.

[9]  Fei Gao,et al.  Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells , 2017, Theranostics.

[10]  S. Goodman,et al.  Inflammation, ageing, and bone regeneration , 2017, Journal of orthopaedic translation.

[11]  J. Bao,et al.  Senescence of mesenchymal stem cells (Review). , 2017, International journal of molecular medicine.

[12]  J. Casal,et al.  Combined miRNA profiling and proteomics demonstrates that different miRNAs target a common set of proteins to promote colorectal cancer metastasis , 2017, The Journal of pathology.

[13]  Xiao-Dong Su,et al.  Optimization of Reference Genes for Normalization of Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction Results in Senescence Study of Mesenchymal Stem Cells. , 2016, Stem cells and development.

[14]  X Zhang,et al.  Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? , 2016, Cell Death and Differentiation.

[15]  Hongling Li,et al.  miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway , 2015, Cell Death and Differentiation.

[16]  Baojie Li,et al.  Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues , 2015, Experimental biology and medicine.

[17]  B. Karadağ,et al.  The prognostic value of circulating microRNAs in heart failure: preliminary results from a genome-wide expression study , 2015, Journal of cardiovascular medicine.

[18]  L. Deng,et al.  Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling. , 2015, Journal of molecular endocrinology.

[19]  Sunghoon Kim,et al.  miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18 , 2014, AGE.

[20]  A. Levine,et al.  MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells , 2014, Oncogene.

[21]  Manuel A. González,et al.  miR‐335 Correlates with Senescence/Aging in Human Mesenchymal Stem Cells and Inhibits Their Therapeutic Actions Through Inhibition of AP‐1 Activity , 2014, Stem cells.

[22]  J. Rossi,et al.  The anti-miR21 antagomir, a therapeutic tool for colorectal cancer, has a potential synergistic effect by perturbing an angiogenesis-associated miR30 , 2014, Front. Genet..

[23]  A. Kho,et al.  MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation , 2013, Cell Death and Differentiation.

[24]  S. Kauppinen,et al.  Treatment of HCV infection by targeting microRNA. , 2013, The New England journal of medicine.

[25]  E. Srour,et al.  The Changing Balance Between Osteoblastogenesis and Adipogenesis in Aging and its Impact on Hematopoiesis , 2013, Current Osteoporosis Reports.

[26]  G. Duda,et al.  Functional Comparison of Chronological and In Vitro Aging: Differential Role of the Cytoskeleton and Mitochondria in Mesenchymal Stromal Cells , 2012, PloS one.

[27]  J. Nathans,et al.  Norrin/Frizzled4 Signaling in Retinal Vascular Development and Blood Brain Barrier Plasticity , 2012, Cell.

[28]  Sun Young Lee,et al.  miR-486-5p induces replicative senescence of human adipose tissue-derived mesenchymal stem cells and its expression is controlled by high glucose. , 2012, Stem cells and development.

[29]  Yu Suk Choi,et al.  Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: Implication to age-associated bone diseases and defects , 2012, Mechanisms of Ageing and Development.

[30]  G. Stein,et al.  MicroRNA control of bone formation and homeostasis , 2012, Nature Reviews Endocrinology.

[31]  T. Wen,et al.  MicroRNAs as a novel cellular senescence regulator , 2012, Ageing Research Reviews.

[32]  A. Dopazo,et al.  miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells , 2011, Cell Death and Differentiation.

[33]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[34]  P. Leprince,et al.  The Wnt/beta‐catenin pathway is activated during advanced arterial aging in humans , 2011, Aging cell.

[35]  R. Knight,et al.  MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines , 2011, Cell cycle.

[36]  Carmen Koch,et al.  How to track cellular aging of mesenchymal stromal cells? , 2010, Aging.

[37]  Wei Liu,et al.  A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. , 2009, The Journal of clinical investigation.

[38]  M. Valenti,et al.  Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis. , 2009, Arthritis and rheumatism.

[39]  Ichiro Takada,et al.  Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis , 2009, Nature Reviews Rheumatology.

[40]  E. Sontheimer,et al.  Origins and Mechanisms of miRNAs and siRNAs , 2009, Cell.

[41]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[42]  Cun-Yu Wang,et al.  Wnt signaling and skeletal development. , 2008, Cellular signalling.

[43]  E. Jones,et al.  Age-related changes in human bone marrow-derived mesenchymal stem cells: Consequences for cell therapies , 2008, Mechanisms of Ageing and Development.

[44]  F. Luciani,et al.  Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. , 2007, Genes & development.

[45]  W. Stanford,et al.  Longitudinal Analysis of Mesenchymal Progenitors and Bone Quality in the Stem Cell Antigen‐1–Null Osteoporotic Mouse , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  Andrea Giustina,et al.  Mechanisms of anabolic therapies for osteoporosis. , 2007, The New England journal of medicine.

[47]  C. Kuo,et al.  Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging , 2007, Science.

[48]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[49]  O. MacDougald,et al.  Regulation of bone mass by Wnt signaling. , 2006, The Journal of clinical investigation.

[50]  Techung Lee,et al.  Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture , 2005, Journal of cellular physiology.

[51]  Q. Han,et al.  Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. , 2005, Biochemical and biophysical research communications.

[52]  Hendrik C Korswagen,et al.  Functional Interaction Between ß-Catenin and FOXO in Oxidative Stress Signaling , 2005, Science.

[53]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[54]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[55]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[56]  Masashi Narita,et al.  Reversal of human cellular senescence: roles of the p53 and p16 pathways , 2003, The EMBO journal.

[57]  Gideon A. Rodan,et al.  Control of osteoblast function and regulation of bone mass , 2003, Nature.

[58]  David L. Lacey,et al.  Osteoclast differentiation and activation , 2003, Nature.

[59]  Jean Y. J. Wang,et al.  Coordinated regulation of life and death by RB , 2003, Nature Reviews Cancer.

[60]  J. Manfredi,et al.  Multiple roles of the tumor suppressor p53 , 2002, Current opinion in oncology.

[61]  J. Glowacki,et al.  Age‐related decline in the osteogenic potential of human bone marrow cells cultured in three‐dimensional collagen sponges , 2001, Journal of cellular biochemistry.

[62]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[63]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[64]  M. Long,et al.  Three-dimensional cellular development is essential for ex vivo formation of human bone , 2000, Nature Biotechnology.

[65]  M. Mastrogiacomo,et al.  Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: Implications for their use in cell therapy. , 2000, Experimental hematology.

[66]  J. Rodríguez,et al.  Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cells dynamics , 1999, Journal of cellular biochemistry.

[67]  G. Karsenty,et al.  Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation , 1997, Cell.

[68]  Jeremy Nathans,et al.  A new member of the frizzled family from Drosophila functions as a Wingless receptor , 1996, Nature.

[69]  D. Dufrane.  Impact of age on human adipose stem cells for bone tissue engineering. , 2017, Cell transplantation.

[70]  M. Kassem,et al.  Assessment of bone formation capacity using in vivo transplantation assays: procedure and tissue analysis. , 2008, Methods in molecular biology.

[71]  F. Dagnaes-hansen,et al.  Aged Human Bone Marrow Stromal Cells Maintaining Bone Forming Capacity in vivo Evaluated Using an Improved Method of Visualization , 2004, Biogerontology.

[72]  Randall T Moon,et al.  WNT and beta-catenin signalling: diseases and therapies. , 2004, Nature reviews. Genetics.

[73]  N. Endo,et al.  Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation , 1999, Journal of Bone and Mineral Metabolism.

[74]  H. Minne.  Osteoporosis in the elderly , 1989, Zeitschrift fur Rheumatologie.