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Gene expression in human mesenchymal stem cell aging cultures: modulation by short peptides

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Abstract

Effects of the short peptides Ala-Glu-Asp (AED), Lys-Glu-Asp (KED) and Lys-Glu (KE) on the expression of IGF1, FOXO1, TERT, TNKS2, and NFκB genes were studied in human embryo bone marrow mesenchymal stem cells (line FetMSCs) variously aged in “passages” or “stationary” cultures. Both cell aging models were similar in gene expression. The main difference was in the TERT gene expression level, which showed an eightfold increase at the “stationary” aging. IGF1 gene expression levels were very similar in both cell culture aging models, being enhanced by 3.5–5.6 fold upon the addition of the peptides. The FOXO1 gene was expressed twice more actively in the “stationary” than in the “passages” aging model. KED peptide inhibited FOXO1 gene expression by 1.6–2.3 fold. KE peptide increased FOXO1 gene expression by about two-fold in the “stationary” aging model but did not affect it in the “passage” aging model. The most striking difference in the peptide effect on cell aging between “passages” and “stationary” aging models was in the KED effects on TNKS2 gene expression; this expression was inhibited by KED in the “passages” model, while stimulation was observed in the “stationary” model. AED, KED, and KE stimulated expression of the NFκB gene in both models. Thus, the peptides studied at nanomolar concentrations modulate the expression of some genes known to be involved in cell aging.

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References

  1. Ashapkin VV, Kutueva LI, Vanyushin BF (2017) Aging as an epigenetic phenomenon. Curr Genomics 18:385–407. https://doi.org/10.2174/1389202918666170412112130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Venugopal P, Balasubramanian S, Majumdar A, Malancha T (2011) Isolation, characterization, and gene expression analysis of Wharton’s jelly-derived mesenchymal stem cells under xeno-free culture conditions. Stem Cells Cloning: Adv Appl 4:39–50. https://doi.org/10.2147/SCCAA.S17548

    Article  CAS  Google Scholar 

  3. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P, Ho AD (2009) Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS ONE 4:e5846. https://doi.org/10.1371/journal.pone.0005846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schellenberg A, Lin Q, Schüler H, Koch CM, Joussen S, Denecke B, Walenda G, Pallua N, Suschek CV, Zenke M, Wagner W (2011) Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks. Aging 3:883–886

    Article  Google Scholar 

  7. Zeng X (2007) Human embryonic stem cells: mechanisms to escape replicative senescence? Stem Cell Rev 3:270–279

    Article  Google Scholar 

  8. Leontieva OV, Demidenko ZN, Blagosklonny MV (2014) Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Proc Natl Acad Sci USA 111:8832–8837. https://doi.org/10.1073/pnas.1405723111

    Article  CAS  PubMed  Google Scholar 

  9. Leontieva OV, Demidenko ZN, Blagosklonny MV (2015) Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program). Oncotarget 6:23238–23248

    Article  Google Scholar 

  10. van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. https://doi.org/10.1038/nature13193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cheung TH, Rando TA (2013) Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol 14:329–340. https://doi.org/10.1038/nrm3591

    Article  CAS  PubMed  Google Scholar 

  12. Lin’kova NS, Drobintseva AO, Orlova OA, Kuznetsova EP, Polyakova VO, Kvetnoy IM, Khavinson VK (2016) Peptide regulation of skin fibroblast functions during their aging in vitro. Bull Exp Biol Med 161:175–178. https://doi.org/10.1007/s10517-016-3370-x

    Article  CAS  PubMed  Google Scholar 

  13. Caputi S, Trubiani O, Bruna S, Trofimova S, Diomede F, Linkova N, Diatlova A, Khavinson V (2019) Effect of short peptides on neuronal differentiation of stem cells. Int J Immunapathol Pharmacol 33:1–12. https://doi.org/10.1177/2058738419828613

    Article  Google Scholar 

  14. Khavinson V, Linkova N, Diatlova A, Trofimova S (2020) Peptide regulation of cell differentiation. Stem Cell Rev Rep 16:118–125. https://doi.org/10.1007/s12015-019-09938-8

    Article  CAS  PubMed  Google Scholar 

  15. Sinjari B, Diomede F, Khavinson V, Mironova E, Linkova N, Trofimova S, Trubiani O, Caputi S (2020) Short peptides protect oral stem cells from ageing. Stem Cell Rev Rep 16:159–166. https://doi.org/10.1007/s12015-019-09921-3

    Article  PubMed  Google Scholar 

  16. Kolchina N, Khavinson V, Linkova N, Yakimov A, Baitin D, Afanasyeva A, Petukhov M (2019) Systematic search for structural motifs of peptide binding to double-stranded DNA. Nucleic Acids Res 47:10553–10563. https://doi.org/10.1093/nar/gkz850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Krylova TA, Kol'tsova AM, Zenin VV, Musorina AS, Iakovleva TK, Polianskaia GG (2012) Comparative characteristics of new mesenchymal stem cell lines derived from human embryonic stem cells, bone marrow and foreskin. Tsitologiia 54:5–16

    CAS  PubMed  Google Scholar 

  18. Khokhlov AN (2013) Impairment of regeneration in aging: appropriateness or stochastics? Biogerontology 14:703–708. https://doi.org/10.1007/s10522-013-9468-x

    Article  CAS  PubMed  Google Scholar 

  19. Shilovsky GA, Shram SI, Morgunova GV, Khokhlov AN (2017) Protein poly(ADP-ribosyl)ation system: changes in development and aging as well as due to restriction of cell proliferation. Biochemistry 82:1391–1401. https://doi.org/10.1134/S0006297917110177

    Article  CAS  PubMed  Google Scholar 

  20. Chia DJ (2014) Minireview: mechanisms of growth hormone-mediated gene regulation. Mol Endocrinol 28:1012–1025. https://doi.org/10.1210/me.2014-1099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bartke A (2005) Minireview: Role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146:3718–3723

    Article  CAS  Google Scholar 

  22. Suh Y, Atzmon G, Cho M-O, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 105:3438–3442. https://doi.org/10.1073/pnas.0705467105

    Article  PubMed  Google Scholar 

  23. Mukhopadhyay A, Oh SW, Tissenbaum HA (2006) Worming pathways to and from DAF-16/FOXO. Exp Gerontol 41:928–934

    Article  CAS  Google Scholar 

  24. Sin TK, Yung BY, Siu PM (2015) Modulation of SIRT1-Foxo1 signaling axis by resveratrol: implications in skeletal muscle aging and insulin resistance. Cell Physiol Biochem 35:541–552. https://doi.org/10.1159/000369718

    Article  CAS  PubMed  Google Scholar 

  25. Kousteni S (2012) FoxO1, the transcriptional chief of staff of energy metabolism. Bone 50:437–443. https://doi.org/10.1016/j.bone.2011.06.034

    Article  CAS  PubMed  Google Scholar 

  26. Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF, Lim R, Zimmermann B, Aspalter IM, Franco CA, Boettger T, Braun T, Fruttiger M, Rajewsky K, Keller C, Brüning JC, Gerhardt H, Carmeliet P, Potente M (2016) FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529:216–220. https://doi.org/10.1038/nature16498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Higuchi M, Dusting GJ, Peshavariya H, Jiang F, Hsiao ST, Chan EC, Liu GS (2013) Differentiation of human adipose-derived stem cells into fat involves reactive oxygen species and Forkhead box O1 mediated upregulation of antioxidant enzymes. Stem Cells Dev 22:878–888. https://doi.org/10.1089/scd.2012.0306

    Article  CAS  PubMed  Google Scholar 

  28. Yun H, Park S, Kim MJ, Yang WK, Im DU, Yang KR, Hong J, Choe W, Kang I, Kim SS, Ha J (2014) AMP-activated protein kinase mediates the antioxidant effects of resveratrol through regulation of the transcription factor FoxO1. FEBS J 281:4421–4438. https://doi.org/10.1111/febs.12949

    Article  CAS  PubMed  Google Scholar 

  29. Klotz LO, Sanchez-Ramos C, Prieto-Arroyo I, Urbanek P, Steinbrenner H, Monsalve M (2015) Redox regulation of FoxO transcription factors. Redox Biol 6:51–72. https://doi.org/10.1016/j.redox.2015.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xing YQ, Li A, Yang Y, Li XX, Zhang LN, Guo HC (2018) The regulation of FOXO1 and its role in disease progression. Life Sci 193:124–131. https://doi.org/10.1016/j.lfs.2017.11.030

    Article  CAS  PubMed  Google Scholar 

  31. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352

    Article  CAS  Google Scholar 

  32. Gonzalez-Suarez E, Samper E, Ramirez A, Flores JM, Martin-Caballero J, Jorcano JL, Blasco MA (2001) Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J 20:2619–2630

    Article  CAS  Google Scholar 

  33. Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21:564–579

    Article  CAS  Google Scholar 

  34. Hsiao SJ, Smith S (2008) Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90:83–92

    Article  CAS  Google Scholar 

  35. Haikarainen T, Krauss S, Lehtio L (2014) Tankyrases: structure, function and therapeutic implications in cancer. Curr Pharm Des 20:6472–6488

    Article  CAS  Google Scholar 

  36. Chiang YJ, Hsiao SJ, Yver D, Cushman SW, Tessarollo L, Smith S, Hodes RJ (2008) Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS ONE 3:e2639. https://doi.org/10.1371/journal.pone.0002639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC (2017) Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 26:460–474. https://doi.org/10.1016/j.cmet.2017.07.019

    Article  CAS  PubMed  Google Scholar 

  38. Ashapkin VV, Linkova NS, Khavinson VKh, Vanyushin BF (2015) Epigenetic mechanisms of peptidergic regulation of gene expression during aging of human cells. Biochemistry (Moscow) 80(3):374–388. https://doi.org/10.1134/S0006297915030062

    Article  CAS  Google Scholar 

  39. Adler AS, Sinha S, Kawahara TLA, Zhang JY, Segal E, Chang HY (2007) Motif module map reveals enforcement of aging by continual NF-κB activity. Genes Dev 21:3244–3257

    Article  CAS  Google Scholar 

  40. Zhang Q, Lenardo MJ, Baltimore D (2017) 30 Years of NF-κB: a blossoming of relevance to human pathobiology. Cell 168:37–57. https://doi.org/10.1016/j.cell.2016.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Natalia Linkova.

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Ashapkin, V., Khavinson, V., Shilovsky, G. et al. Gene expression in human mesenchymal stem cell aging cultures: modulation by short peptides. Mol Biol Rep 47, 4323–4329 (2020). https://doi.org/10.1007/s11033-020-05506-3

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