Skip to main content
Log in

Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

An Erratum to this article was published on 12 April 2017

Abstract

Nanomaterials are increasingly used for biomedical applications; thus, it is important to understand their biological effects. Previous studies suggested that magnetic iron oxide nanoparticles (IONPs) have tissue-repairing effects. In the present study, we explored cellular effects of IONPs in mesenchymal stem cells (MSCs) and identified the underlying molecular mechanisms. The results showed that our as-prepared IONPs were structurally stable in MSCs and promoted osteogenic differentiation of MSCs as whole particles. Moreover, at the molecular level, we compared the gene expression of MSCs with or without IONP exposure and showed that IONPs upregulated long noncoding RNA INZEB2, which is indispensable for maintaining osteogenesis by MSCs. Furthermore, overexpression of INZEB2 downregulated ZEB2, a factor necessary to repress BMP/Smad-dependent osteogenic transcription. We also demonstrated that the essential role of INZEB2 in osteogenic differentiation was ZEB2-dependent. In summary, we elucidated the molecular basis of IONPs’ effects on MSCs; these findings may serve as a meaningful theoretical foundation for applications of stem cells to regenerative medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Wang, F. F.; Zhai, D.; Wu, C. T.; Chang, J. Multifunctional mesoporous bioactive glass/upconversion nanoparticle nanocomposites with strong red emission to monitor drug delivery and stimulate osteogenic differentiation of stem cells. Nano Res. 2016, 9, 1193–1208.

    Article  Google Scholar 

  2. Weightman, A. P.; Jenkins, S. I.; Chari, D. M. Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake. Nano Res. 2016, 9, 2384–2397.

    Article  Google Scholar 

  3. Zhang, S.; Bach-Gansmo, F. L.; Xia, D.; Besenbacher, F.; Birkedal, H.; Dong, M. D. Nanostructure and mechanical properties of the osteocyte lacunar-canalicular networkassociated bone matrix revealed by quantitative nanomechanical mapping. Nano Res. 2015, 8, 3250–3260.

    Article  Google Scholar 

  4. Henstock, J. R.; Rotherham, M.; Rashidi, H.; Shakesheff, K. M.; El Haj, A. J. Remotely activated mechanotransduction via magnetic nanoparticles promotes mineralization synergistically with bone morphogenetic protein 2: Applications for injectable cell therapy. Stem Cells Transl. Med. 2014, 3, 1363–1374.

    Article  Google Scholar 

  5. Bock, N.; Riminucci, A.; Dionigi, C.; Russo, A.; Tampieri, A.; Landi, E.; Goranov, V. A.; Marcacci, M.; Dediu, V. A novel route in bone tissue engineering: Magnetic biomimetic scaffolds. Acta Biomater. 2010, 6, 786–796.

    Article  Google Scholar 

  6. Yun, H. M.; Ahn, S. J.; Park, K. R.; Kim, M. J.; Kim, J. J.; Jin, G. Z.; Kim, H. W.; Kim, E. C. Magnetic nanocomposite scaffolds combined with static magnetic field in the stimulation of osteoblastic differentiation and bone formation. Biomaterials 2016, 85, 88–98.

    Article  Google Scholar 

  7. Meng, J.; Xiao, B.; Zhang, Y.; Liu, J.; Xue, H. D.; Lei, J.; Kong, H.; Huang, Y. G.; Jin, Z. Y.; Gu, N. et al. Superparamagnetic responsive nanofibrous scaffolds under static magnetic field enhance osteogenesis for bone repair in vivo. Sci. Rep. 2013, 3, 2655.

    Google Scholar 

  8. Heymer, A.; Haddad, D.; Weber, M.; Gbureck, U.; Jakob, P. M.; Eulert, J.; Noeth, U. Iron oxide labelling of human mesenchymal stem cells in collagen hydrogels for articular cartilage repair. Biomaterials 2008, 29, 1473–1483.

    Article  Google Scholar 

  9. Dzamukova, M. R.; Naumenko, E. A.; Rozhina, E. V.; Trifonov, A. A.; Fakhrullin, R. F. Cell surface engineering with polyelectrolyte-stabilized magnetic nanoparticles: A facile approach for fabrication of artificial multicellular tissue-mimicking clusters. Nano Res. 2015, 8, 2515–2532.

    Article  Google Scholar 

  10. Marie, P. J. Targeting integrins to promote bone formation and repair. Nat. Rev. Endocrinol. 2013, 9, 288–295.

    Article  Google Scholar 

  11. Sun, J. F.; Liu, X.; Huang, J. Q.; Song, L.; Chen, Z. H.; Liu, H. Y.; Li, Y.; Zhang, Y.; Gu, N. Magnetic assemblymediated enhancement of differentiation of mouse bone marrow cells cultured on magnetic colloidal assemblies. Sci. Rep. 2014, 4, 5125.

    Google Scholar 

  12. Yang, F.; Li, M. X.; Cui, H. T.; Wang, T. T.; Chen, Z. W.; Song, L.; Gu, Z. X.; Zhang, Y.; Gu, N. Altering the response of intracellular reactive oxygen to magnetic nanoparticles using ultrasound and microbubbles. Sci. China Mater. 2015, 58, 467–480.

    Article  Google Scholar 

  13. Yang, Z. Z.; Ding, X. G.; Jiang, J. Facile synthesis of magnetic–plasmonic nanocomposites as T1 MRI contrast enhancing and photothermal therapeutic agents. Nano Res. 2016, 9, 787–799.

    Article  Google Scholar 

  14. Liu, D.; Yang, F.; Xiong, F.; Gu, N. The smart drug delivery system and its clinical potential. Theranostics 2016, 6, 1306–1323.

    Article  Google Scholar 

  15. Chen, Y. C.; Hsiao, J. K.; Liu, H. M.; Lai, I. Y.; Yao, M.; Hsu, S. C.; Ko, B. S.; Chen, Y. C.; Yang, C. S.; Huang, D. M. The inhibitory effect of superparamagnetic iron oxide nanoparticle (ferucarbotran) on osteogenic differentiation and its signaling mechanism in human mesenchymal stem cells. Toxicol. Appl. Pharmacol. 2010, 245, 272–279.

    Article  Google Scholar 

  16. Wang, Q. W.; Chen, B.; Cao, M.; Sun, J. F.; Wu, H.; Zhao, P.; Xing, J.; Yang, Y.; Zhang, X. Q.; Ji, M. et al. Response of MAPK pathway to iron oxide nanoparticles in vitro treatment promotes osteogenic differentiation of hBMSCs. Biomaterials 2016, 86, 11–20.

    Article  Google Scholar 

  17. Assa, F.; Jafarizadeh-Malmiri, H.; Ajamein, H.; Anarjan, N.; Vaghari, H.; Sayyar, Z.; Berenjian, A. A biotechnological perspective on the application of iron oxide nanoparticles. Nano Res. 2016, 9, 2203–2225.

    Article  Google Scholar 

  18. Williams, D. F. On the mechanisms of biocompatibility. Biomaterials 2008, 29, 2941–2953.

    Article  Google Scholar 

  19. Klapperich, C. M.; Bertozzi, C. R. Global gene expression of cells attached to a tissue engineering scaffold. Biomaterials 2004, 25, 5631–5641.

    Article  Google Scholar 

  20. Cheng, K.; Shen, D. L.; Hensley, M. T.; Middleton, R.; Sun, B. M.; Liu, W. X.; de Couto, G.; Marbán, E. Magnetic antibody-linked nanomatchmakers for therapeutic cell targeting. Nat. Commun. 2014, 5, 4880.

    Article  Google Scholar 

  21. Pan, Y. M.; Wang, L. M.; Kang, S. G.; Lu, Y. Y.; Yang, Z. X.; Huynh, T.; Chen, C. Y.; Zhou, R. H.; Guo, M. Z.; Zhao, Y. L. Gd-metallofullerenol nanomaterial suppresses pancreatic cancer metastasis by inhibiting the interaction of histone deacetylase 1 and metastasis-associated protein 1. ACS Nano 2015, 9, 6826–6836.

    Article  Google Scholar 

  22. Nair, A. V.; Keliher, E. J.; Core, A. B.; Brown, D.; Weissleder, R. Characterizing the interactions of organic nanoparticles with renal epithelial cells in vivo. ACS Nano 2015, 9, 3641–3653.

    Article  Google Scholar 

  23. Eddy, S. R. Non-coding RNA genes and the modern RNA world. Nat. Rev. Genet. 2001, 2, 919–929.

    Article  Google Scholar 

  24. Carninci, P.; Kasukawa, T.; Katayama, S.; Gough, J.; Frith, M. C.; Maeda, N.; Oyama, R.; Ravasi, T.; Lenhard, B.; Wells, C. et al. The transcriptional landscape of the mammalian genome. Science 2005, 309, 1559–1563.

    Article  Google Scholar 

  25. Geisler, S.; Coller, J. RNA in unexpected places: Long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell Biol. 2013, 14, 699–712.

    Article  Google Scholar 

  26. Quinn, J. J.; Chang, H. Y. Unique features of long noncoding RNA biogenesis and function. Nat. Rev. Genet. 2016, 17, 47–62.

    Article  Google Scholar 

  27. Ørom, U. A.; Derrien, T.; Beringer, M.; Gumireddy, K.; Gardini, A.; Bussotti, G.; Lai, F.; Zytnicki, M.; Notredame, C.; Huang, Q. H. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 2010, 143, 46–58.

    Article  Google Scholar 

  28. Fatica, A.; Bozzoni, I. Long non-coding RNAs: New players in cell differentiation and development. Nat. Rev. Genet. 2014, 15, 7–21.

    Article  Google Scholar 

  29. Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 2012, 338, 1435–1439.

    Article  Google Scholar 

  30. Chen, B.; Li, Y.; Zhang, X. Q.; Liu, F.; Liu, Y. L.; Ji, M.; Xiong, F.; Gu, N. An efficient synthesis of ferumoxytol induced by alternating-current magnetic field. Mater. Lett. 2016, 170, 93–96.

    Article  Google Scholar 

  31. Ma, M.; Zhang, Y.; Shen, X. L.; Xie, J.; Li, Y.; Gu, N. Targeted inductive heating of nanomagnets by a combination of alternating current (AC) and static magnetic fields. Nano Res. 2015, 8, 600–610.

    Article  Google Scholar 

  32. Lin, X. B.; Gu, N. Surface properties of encapsulating hydrophobic nanoparticles regulate the main phase transition temperature of lipid bilayers: A simulation study. Nano Res. 2014, 7, 1195–1204.

    Article  Google Scholar 

  33. Tian, F.; Chen, G. C.; Yi, P. W.; Zhang, J. C.; Li, A. G.; Zhang, J.; Zheng, L. R.; Deng, Z.W.; Shi, Q.; Peng, R. et al. Fates of Fe3O4 and Fe3O4@SiO2 nanoparticles in human mesenchymal stem cells assessed by synchrotron radiationbased techniques. Biomaterials 2014, 35, 6412–6421.

    Article  Google Scholar 

  34. Sun, M.; Zhang, G.; Liu, H. J.; Liu, Y.; Li, J. H. a-and Fe2O3 nanoparticle/nitrogen doped carbon nanotube catalysts for high-performance oxygen reduction reaction. Sci. China Mater. 2015, 58, 683–692.

    Article  Google Scholar 

  35. Ashburner, M.; Ball, C. A.; Blake, J. A.; Botstein, D.; Butler, H.; Cherry, J. M.; Davis, A. P.; Dolinski, K.; Dwight, S. S.; Eppig, J. T. et al. Gene ontology: Tool for the unification of biology. Nat. Genet. 2000, 25, 25–29.

    Article  Google Scholar 

  36. Huang da, W.; Sherman, B. T.; Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 2009, 4, 44–57.

    Article  Google Scholar 

  37. Kanchanawong, P.; Shtengel, G.; Pasapera, A. M.; Ramko, E. B.; Davidson, M. W.; Hess, H. F.; Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 2010, 468, 580–584.

    Article  Google Scholar 

  38. Jaiswal, R. K.; Jaiswal, N.; Bruder, S. P.; Mbalaviele, G.; Marshak, D. R.; Pittenger, M. F. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J. Biol. Chem. 2000, 275, 9645–9652.

    Article  Google Scholar 

  39. Zahanich, I.; Graf, E. M.; Heubach, J. F.; Hempel, U.; Boxberger, S.; Ravens, U. Molecular and functional expression of voltage-operated calcium channels during osteogenic differentiation of human mesenchymal stem cells. J. Bone. Miner. Res. 2005, 20, 1637–1646.

    Article  Google Scholar 

  40. Ge, C. X.; Xiao, G. Z.; Jiang, D.; Franceschi, R. T. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell. Biol. 2007, 176, 709–718.

    Article  Google Scholar 

  41. Bikle, D. D.; Tahimic, C.; Chang, W. H.; Wang, Y. M.; Philippou, A.; Barton, E. R. Role of IGF-I signaling in muscle bone interactions. Bone 2015, 80, 79–88.

    Article  Google Scholar 

  42. Marie, P. J.; Lomri, A.; Sabbagh, A.; Basle, M. Culture and behavior of osteoblastic cells isolated from normal trabecular bone surfaces. In Vitro Cell. Dev. Biol. 1989, 25, 373–380.

    Article  Google Scholar 

  43. Pockwinse, S. M.; Wilming, L. G.; Conlon, D. M.; Stein, G. S.; Lian, J. B. Expression of cell growth and bone specific genes at single cell resolution during development of bone tissue-like organization in primary osteoblast cultures. J. Cell. Biochem. 1992, 49, 310–323.

    Article  Google Scholar 

  44. Bae, J. S.; Gutierrez, S.; Narla, R.; Pratap, J.; Devados, R.; van Wijnen, A. J.; Stein, J. L.; Stein, G. S.; Lian, J. B.; Javed, A. Reconstitution of Runx2/Cbfa1-null cells identifies a requirement for BMP2 signaling through a Runx2 functional domain during osteoblast differentiation. J. Cell. Biochem. 2007, 100, 434–449.

    Article  Google Scholar 

  45. Wu, M. R.; Chen, G. Q.; Li, Y.-P. TGF-ß and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016, 4, 16009.

    Article  Google Scholar 

  46. Nikukar, H.; Reid, S.; Tsimbouri, P. M.; Riehle, M. O.; Curtis, A. S. G.; Dalby, M. J. Osteogenesis of mesenchymal stem cells by nanoscale mechanotransduction. ACS Nano 2013, 7, 2758–2767.

    Article  Google Scholar 

  47. Yi, C. Q.; Liu, D. D.; Fong, C. C.; Zhang, J. C.; Yang, M. S. Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 MAPK pathway. ACS Nano 2010, 4, 6439–6448.

    Article  Google Scholar 

  48. Young, M. F.; Kerr, J. M.; Ibaraki, K.; Heegaard, A. M.; Robey, P. G. Structure, expression, and regulation of the major noncollagenous matrix proteins of bone. Clin. Orthop. Relat. Res. 1992, 275–294.

    Google Scholar 

  49. Robey, P. G.; Fedarko, N. S.; Hefferan, T. E.; Bianco, P.; Vetter, U. K.; Grzesik, W.; Friedenstein, A.; van der Pluijm, G.; Mintz, K. P.; Young, M. F. et al. Structure and molecular regulation of bone matrix proteins. J. Bone Miner. Res. 1993, 8, S483–487.

    Article  Google Scholar 

  50. Komori, T.; Yagi, H.; Nomura, S.; Yamaguchi, A.; Sasaki, K.; Deguchi, K.; Shimizu, Y.; Bronson, R. T.; Gao, Y. H.; Inada, M. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997, 89, 755–764.

    Article  Google Scholar 

  51. Otto, F.; Thornell, A. P.; Crompton, T.; Denzel, A.; Gilmour, K. C.; Rosewell, I. R.; Stamp, G. W. H.; Beddington, R. S. P.; Mundlos, S.; Olsen, B. R. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997, 89, 765–771.

    Article  Google Scholar 

  52. Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J. 2003, 22, 2443–2452.

    Article  Google Scholar 

  53. van Grunsven, L. A.; Schellens, A.; Huylebroeck, D.; Verschueren, K. SIP1 (Smad interacting protein 1) and deltaEF1 (delta-crystallin enhancer binding factor) are structurally similar transcriptional repressors. J. Bone Joint Surg. Am. 2001, 83-A, S40–S47.

    Google Scholar 

  54. Verschueren, K.; Remacle, J. E.; Collart, C.; Kraft, H.; Baker, B. S.; Tylzanowski, P.; Nelles, L.; Wuytens, G.; Su, M. T.; Bodmer, R. et al. SIP1, a novel zinc finger/ homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes. J. Biol. Chem. 1999, 274, 20489–20498.

    Article  Google Scholar 

  55. Postigo, A. A.; Depp, J. L.; Taylor, J. J.; Kroll, K. L. Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J. 2003, 22, 2453–2462.

    Article  Google Scholar 

  56. Kirschvink, J. L.; Walker, M. M.; Diebel, C. E. Magnetitebased magnetoreception. Curr. Opin. Neurobiol. 2001, 11, 462–467.

    Article  Google Scholar 

  57. Winklhofer, M.; Kirschvink, J. L. A quantitative assessment of torque-transducer models for magnetoreception. J. R. Soc. Interface 2010, 7, S273–S289.

    Article  Google Scholar 

  58. Stanley, S. A.; Sauer, J.; Kane, R. S.; Dordick, J. S.; Friedman, J. M. Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles. Nat. Med. 2015, 21, 92–98.

    Article  Google Scholar 

  59. Guilak, F.; Cohen, D. M.; Estes, B. T.; Gimble, J. M.; Liedtke, W.; Chen, C. S. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 2009, 5, 17–26.

    Article  Google Scholar 

  60. Wang, N.; Tytell, J. D.; Ingber, D. E. Mechanotransduction at a distance: Mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 2009, 10, 75–82.

    Article  Google Scholar 

  61. Mahmoudi, M.; Laurent, S.; Shokrgozar, M. A.; Hosseinkhani, M. Toxicity evaluations of superparamagnetic iron oxide nanoparticles: Cell “vision” versus physicochemical properties of nanoparticles. ACS Nano 2011, 5, 7263–7276.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Basic Research Program of China (Nos. 2013CB733804 and 2013CB934400), the National Natural Science Foundation of China (NSFC) for Key Project of International Cooperation (No. 61420106012), Special Project on Development of National Key Scientific Instruments and Equipment of China (No. 2011YQ03013403), the Natural Science Foundation of Jiangsu Province (No. BK20130608), the Fundamental Research Funds for the Central Universities and the Graduate Research and Innovation Program of Jiangsu Province in China (No. KYLX15-0167).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ning Gu.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s12274-017-1566-7.

Electronic supplementary material

12274_2016_1322_MOESM1_ESM.pdf

Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Chen, B., Ma, F. et al. Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2 . Nano Res. 10, 626–642 (2017). https://doi.org/10.1007/s12274-016-1322-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-016-1322-4

Keywords

Navigation