Abstract
Aging is a major risk factor for degenerative joint diseases, such as osteoarthritis (OA). Previous studies have confirmed the link between senescent mesenchymal stem cells (MSCs) and OA. Cartilage-derived stem/progenitor cells (CSPCs) with MSCs properties have been extracted from a variety of species. We inferred that the senescence of CSPCs may promote the development of osteoarthritis. However, the cellular and molecular mechanisms of CSPCs senescence remains unknown. In this study, we investigated the role of JAK-STAT signaling pathway in a replicative senescence model of CSPCs. We showed that the late CSPCs (> 15th passage) exhibited distinct senescent phenotypes, including increased proportion of β-gal positive senescent cells and F-actin content, as well as cell cycle arrest. In late CSPCs, the activity of JAK-STAT signaling pathway was significantly increased. Activation of JAK-STAT signaling pathway promoted cell senescence in early CSPCs (< 6th passage). Conversely, pharmacological inhibition or genetic knockdown of JAK-STAT signaling pathway attenuated cell senescence in late CSPCs. In conclusion, our results demonstrated the critical role of JAK-STAT signaling pathway in CSPCs senescence.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189. https://doi.org/10.1038/nature16932
Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R (2000) Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: Implications for their use in cell therapy. Exp Hematol 28:707–715. https://doi.org/10.1016/s0301-472x(00)00160-0
Barrat FJ, Crow MK, Ivashkiv LB (2019) Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol 20:1574–1583. https://doi.org/10.1038/s41590-019-0466-2
Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I (2004) Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22:675–682. https://doi.org/10.1634/stemcells.22-5-675
Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7:14. https://doi.org/10.1186/1471-2121-7-14
Brandl A, Angele P, Roll C, Prantl L, Kujat R, Kinner B (2010) Influence of the growth factors PDGF-BB, TGF-beta1 and bFGF on the replicative aging of human articular chondrocytes during in vitro expansion. J Orthop Res 28:354–360. https://doi.org/10.1002/jor.21007
Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740. https://doi.org/10.1038/nrm2233
Cechella JL, Leite MR, Dobrachinski F, da Rocha JT, Carvalho NR, Duarte MM, Soares FA, Bresciani G, Royes LF, Zeni G (2014) Moderate swimming exercise and caffeine supplementation reduce the levels of inflammatory cytokines without causing oxidative stress in tissues of middle-aged rats. Amino Acids 46:1187–1195. https://doi.org/10.1007/s00726-014-1679-1
Chen M, Xiao L, Dai G, Lu P, Zhang Y, Li Y, Ni M, Rui Y (2021) Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells. Front Cell Dev Biol 9:650250. https://doi.org/10.3389/fcell.2021.650250
Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ (1999) Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol 107:275–281. https://doi.org/10.1046/j.1365-2141.1999.01715.x
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367. https://doi.org/10.1073/pnas.92.20.9363
Fu L, Hu Y, Song M, Liu Z, Zhang W, Yu FX, Wu J, Wang S, Izpisua Belmonte JC, Chan P, Qu J, Tang F, Liu GH (2019) Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biol 17:e3000201. https://doi.org/10.1371/journal.pbio.3000201
Goropevsek A, Holcar M, Avcin T (2017) The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus. Clin Rev Allergy Immunol 52:164–181. https://doi.org/10.1007/s12016-016-8550-y
Hayflick L (1965) The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res 37:614–636. https://doi.org/10.1016/0014-4827(65)90211-9
Herrera SC, Bach EA (2019) JAK/STAT signaling in stem cells and regeneration: from Drosophila to vertebrates. Development 146. https://doi.org/10.1242/dev.167643
Hormoz S (2013) Stem cell population asymmetry can reduce rate of replicative aging. J Theor Biol 331:19–27. https://doi.org/10.1016/j.jtbi.2013.04.018
Ji J, Wu Y, Meng Y, Zhang L, Feng G, Xia Y, Xue W, Zhao S, Gu Z, Shao X (2017) JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients. Acta Biochim Biophys Sin (Shanghai) 49:208–215. https://doi.org/10.1093/abbs/gmw134
Jiang Y, Tuan RS (2015) Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol 11:206–212. https://doi.org/10.1038/nrrheum.2014.200
Kim KS, Kang KW, Seu YB, Baek SH, Kim JR (2009) Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev 130:179–188. https://doi.org/10.1016/j.mad.2008.11.004
Madeira A, da Silva CL, dos Santos F, Camafeita E, Cabral JM, Sa-Correia I (2012) Human mesenchymal stem cell expression program upon extended ex-vivo cultivation, as revealed by 2-DE-based quantitative proteomics. PLoS ONE 7:e43523. https://doi.org/10.1371/journal.pone.0043523
Malaise O, Tachikart Y, Constantinides M, Mumme M, Ferreira-Lopez R, Noack S, Krettek C, Noel D, Wang J, Jorgensen C, Brondello JM (2019) Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging 11:9128–9146. https://doi.org/10.18632/aging.102379
Martin JA, Buckwalter JA (2001) Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa Orthop J 21:1–7
Martin JA, Buckwalter JA (2002) Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3:257–264. https://doi.org/10.1023/a:1020185404126
Mehrazarin S, Oh JE, Chung CL, Chen W, Kim RH, Shi S, Park NH, Kang MK (2011) Impaired odontogenic differentiation of senescent dental mesenchymal stem cells is associated with loss of Bmi-1 expression. J Endod 37:662–666. https://doi.org/10.1016/j.joen.2011.02.009
Meyer SC, Levine RL (2014) Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res 20:2051–2059. https://doi.org/10.1158/1078-0432.CCR-13-0279
Noer A, Boquest AC, Collas P (2007) Dynamics of adipogenic promoter DNA methylation during clonal culture of human adipose stem cells to senescence. BMC Cell Biol 8:18. https://doi.org/10.1186/1471-2121-8-18
Price FD, von Maltzahn J, Bentzinger CF, Dumont NA, Yin H, Chang NC, Wilson DH, Frenette J, Rudnicki MA (2014) Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat Med 20:1174–1181. https://doi.org/10.1038/nm.3655
Qin Y, Fang K, Lu N, Hu Y, Tian Z, Zhang C (2019) Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling. Stem Cell Res Ther 10:210. https://doi.org/10.1186/s13287-019-1311-0
Ren X, Hu B, Song M, Ding Z, Dang Y, Liu Z, Zhang W, Ji Q, Ren R, Ding J, Chan P, Jiang C, Ye K, Qu J, Tang F, Liu GH (2019) Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis. Cell Rep 26:3643–3656e3647. https://doi.org/10.1016/j.celrep.2019.02.088
Sacitharan PK (2019) Ageing and Osteoarthritis. Subcell Biochem 91:123–159. https://doi.org/10.1007/978-981-13-3681-2_6
Wagner W, Horn P, Castoldi M, Diehlmann A, Bork S, Saffrich R, Benes V, Blake J, Pfister S, Eckstein V, Ho AD (2008) Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS ONE 3:e2213. https://doi.org/10.1371/journal.pone.0002213
Williams R, Khan IM, Richardson K, Nelson L, McCarthy HE, Analbelsi T, Singhrao SK, Dowthwaite GP, Jones RE, Baird DM, Lewis H, Roberts S, Shaw HM, Dudhia J, Fairclough J, Briggs T, Archer CW (2010) Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS ONE 5:e13246. https://doi.org/10.1371/journal.pone.0013246
Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, White TA, Johnson KO, Stout MB, Mezera V, Giorgadze N, Jensen MD, LeBrasseur NK, Kirkland JL (2015) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A 112:E6301–6310. https://doi.org/10.1073/pnas.1515386112
Acknowledgements
This work was supported by Clinical Center Construction Project of Nantong (HS2019004), A Project of Nantong Science and Technology Program (JC2020015); The Research Innovation Program for College Graduates of Jiangsu Province (KYCX20-2800).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ji, T., Chen, M., Sun, W. et al. JAK-STAT signaling mediates the senescence of cartilage-derived stem/progenitor cells. J Mol Histol 53, 635–643 (2022). https://doi.org/10.1007/s10735-022-10086-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-022-10086-6