Advertisement

Effects of minocycline and rapamycin in gamma-irradiated human embryonic stem cells-derived cerebral organoids

  • Antos Shakhbazau
  • Natalya Danilkovich
  • Ihar Seviaryn
  • Tatyana Ermilova
  • Svetlana Kosmacheva
Short Communication
  • 2 Downloads

Abstract

Radiation induces DNA and protein damage and free radical formation, effectively establishing cellular senescence in a variety of models. We demonstrate the effects of two known pleiotropic drugs following gamma radiation damage in neurosphere/cerebral organoid system based on human embryonic stem cells. mTORC1 repression by rapamycin prior to irradiation, or metabolic activation by minocycline after irradiation, partially rescues neuroepithelium integrity, neurite-growing capacity, ventricle formation and extracellular acidification rate as an integral measure of metabolic output. Cerebral organoid model thus provides valid and robust readouts for radiation studies in a complex 3D setting.

Keywords

Radiation Neural development Pluripotent stem cells Cerebral organoids Minocycline Rapamycin 

Notes

Acknowledgements

The authors are grateful to Prof. Yu-Chieh Wang and Victor Lin (UNTHSC) for their training and inspiration in hESCs and organoid work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11033_2018_4552_MOESM1_ESM.docx (2.9 mb)
Supplementary material 1 (DOCX 2966 KB)

References

  1. 1.
    Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379CrossRefGoogle Scholar
  2. 2.
    Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H (2016) Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 22:1101–1107CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Iefremova V, Manikakis G, Krefft O, Jabali A, Weynans K, Wilkens R, Marsoner F, Brandl B, Muller FJ, Koch P, Ladewig J (2017) An organoid-based model of cortical development identifies non-cell-autonomous defects in Wnt signaling contributing to Miller-Dieker syndrome. Cell Rep 19:50–59CrossRefGoogle Scholar
  4. 4.
    Nalapareddy K, Nattamai KJ, Kumar RS, Karns R, Wikenheiser-Brokamp KA, Sampson LL, Mahe MM, Sundaram N, Yacyshyn MB, Yacyshyn B, Helmrath MA, Zheng Y, Geiger H (2017) Canonical Wnt signaling ameliorates aging of intestinal stem cells. Cell Rep 18:2608–2621CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Hu JL, Todhunter ME, LaBarge MA, Gartner ZJ (2018) Opportunities for organoids as new models of aging. J Cell Biol 217:39–50CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Li M, You L, Xue J, Lu Y (2018) Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: a mini review. Front Pharmacol 9:522CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y (2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci USA 110:20284–20289CrossRefGoogle Scholar
  8. 8.
    Shakhbazau A, Lin V, Zolekar A, Mull A, Wang Y Using NGLY1-deficient human pluripotent stem cells to understand congenital deglycosylation disorder-induced neural abnormalities. ISSCR Annual Meeting, p. 496, 14–17 June 2017, BostonGoogle Scholar
  9. 9.
    Shakhbazau A, Shcharbin D, Seviaryn I, Goncharova N, Kosmacheva S, Potapnev M, Bryszewska M, Kumar R, Biernaskie J, Midha R (2012) Dendrimer-driven neurotrophin expression differs in temporal patterns between rodent and human stem cells. Mol Pharm 9:1521–1528CrossRefGoogle Scholar
  10. 10.
    Fritsche E, Gassmann K, Schreiber T (2011) Neurospheres as a model for developmental neurotoxicity testing. Methods Mol Biol 758:99–114CrossRefGoogle Scholar
  11. 11.
    Shakhbazau AV, Shcharbin DG, Goncharova NV, Seviaryn IN, Kosmacheva SM, Kartel NA, Bryszewska M, Majoral JP, Potapnev MP (2011) Neurons and stromal stem cells as targets for polycation-mediated transfection. Bull Exp Biol Med 151:126–129CrossRefGoogle Scholar
  12. 12.
    Witte H, Neukirchen D, Bradke F (2008) Microtubule stabilization specifies initial neuronal polarization. J Cell Biol 180:619–632CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Schmuck MR, Temme T, Dach K, de BD, Barenys, Bendt M, Mosig FA, Fritsche E (2017) Omnisphero: a high-content image analysis (HCA) approach for phenotypic developmental neurotoxicity (DNT) screenings of organoid neurosphere cultures in vitro. Arch Toxicol 91:2017–2028CrossRefGoogle Scholar
  14. 14.
    TeSlaa T, Teitell MA (2014) Techniques to monitor glycolysis. Methods Enzymol 542:91–114CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Yang J, Gong Y, Sontag DP, Corbin I, Minuk GY (2018) Effects of low-density lipoprotein docosahexaenoic acid nanoparticles on cancer stem cells isolated from human hepatoma cell lines. Mol Biol Rep 45(5):1023–1036CrossRefGoogle Scholar
  16. 16.
    Shakhbazau A, Shcharbin D, Petyovka N, Goncharova N, Seviaryn I, Kosmacheva S, Bryszewska M, Potapnev M (2012) Non-virally modified human mesenchymal stem cells produce ciliary neurotrophic factor in biodegradable fibrin-based 3D scaffolds. J Pharm Sci 101:1546–1554CrossRefGoogle Scholar
  17. 17.
    Srikanth L, Sunitha MM, Kumar PS, Chandrasekhar C, Vengamma B, Sarma PV (2016) Gel based in vitro 3D model exploring the osteocytic potentiality of human CD34(+) stem cells. Mol Biol Rep 43:1233–1242CrossRefGoogle Scholar
  18. 18.
    Mostafavi-Pour Z, Ashrafi MR, Talaei-Khozani T (2018) Down regulation of ITGA4 and ITGA5 genes after formation of 3D spherules by human Wharton’s jelly stem cells (hWJSCs). Mol Biol Rep 45:245–252CrossRefGoogle Scholar
  19. 19.
    Chang MY, Rhee YH, Yi SH, Lee SJ, Kim RK, Kim H, Park CH, Lee SH (2014) Doxycycline enhances survival and self-renewal of human pluripotent stem cells. Stem Cell Rep 3:353–364CrossRefGoogle Scholar
  20. 20.
    Caron A, Richard D, Laplante M (2015) The roles of mTOR complexes in lipid metabolism. Annu Rev Nutr 35:321–348CrossRefGoogle Scholar
  21. 21.
    Ehninger D, Neff F, Xie K (2014) Longevity, aging and rapamycin. Cell Mol Life Sci 71:4325–4346CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Wu C, Yang L, Qi X, Wang T, Li M, Xu K (2018) Inhibition of long non-coding RNA HOTAIR enhances radiosensitivity via regulating autophagy in pancreatic cancer. Cancer Manag Res 10:5261–5271CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774CrossRefGoogle Scholar
  24. 24.
    Garrido-Mesa N, Zarzuelo A, Galvez J (2013) What is behind the non-antibiotic properties of minocycline? Pharmacol Res 67:18–30CrossRefGoogle Scholar
  25. 25.
    Shakhbazau A, Mishra M, Chu TH, Brideau C, Cummins K, Tsutsui S, Shcharbin D, Majoral JP, Mignani S, Blanchard-Desce M, Bryszewska M, Yong VW, Stys PK (2015) Fluorescent phosphorus dendrimer as a spectral nanosensor for macrophage polarization and fate tracking in spinal cord injury. Macromol Biosci 15:1523–1534CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Antos Shakhbazau
    • 1
  • Natalya Danilkovich
    • 1
  • Ihar Seviaryn
    • 1
    • 2
  • Tatyana Ermilova
    • 3
  • Svetlana Kosmacheva
    • 1
  1. 1.Republican Scientific and Practical Centre of Transfusion and Medical BiotechnologyMinskBelarus
  2. 2.Alexandrov Republican Scientific and Practical Centre for Oncology and Medical RadiologyMinskBelarus
  3. 3.Belarussian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus

Personalised recommendations