Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2
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An erratum to this article is available online at https://doi.org/10.1007/s12274-017-1566-7
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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.
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Magnetic iron oxide nanoparticles accelerate osteogenic differentiation of mesenchymal stem cells via modulation of long noncoding RNA INZEB2
)
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.
References(61)
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.
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.
Zhang, S.; Bach-Gansmo, F. L.; Xia, D.; Besenbacher, F.; Birkedal, H.; Dong, M. D. Nanostructure and mechanical properties of the osteocyte lacunar-canalicular network- associated bone matrix revealed by quantitative nanomechanical mapping. Nano Res. 2015, 8, 3250–3260.
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.
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.
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.
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. Super- paramagnetic responsive nanofibrous scaffolds under static magnetic field enhance osteogenesis for bone repair in vivo. Sci. Rep. 2013, 3, 2655.
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.
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.
Marie, P. J. Targeting integrins to promote bone formation and repair. Nat. Rev. Endocrinol. 2013, 9, 288–295.
Sun, J. F.; Liu, X.; Huang, J. Q.; Song, L.; Chen, Z. H.; Liu, H. Y.; Li, Y.; Zhang, Y.; Gu, N. Magnetic assembly- mediated enhancement of differentiation of mouse bone marrow cells cultured on magnetic colloidal assemblies. Sci. Rep. 2014, 4, 5125.
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.
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.
Liu, D.; Yang, F.; Xiong, F.; Gu, N. The smart drug delivery system and its clinical potential. Theranostics 2016, 6, 1306–1323.
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.
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.
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.
Williams, D. F. On the mechanisms of biocompatibility. Biomaterials 2008, 29, 2941–2953.
Klapperich, C. M.; Bertozzi, C. R. Global gene expression of cells attached to a tissue engineering scaffold. Biomaterials 2004, 25, 5631–5641.
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.
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.
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.
Eddy, S. R. Non-coding RNA genes and the modern RNA world. Nat. Rev. Genet. 2001, 2, 919–929.
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.
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.
Quinn, J. J.; Chang, H. Y. Unique features of long non- coding RNA biogenesis and function. Nat. Rev. Genet. 2016, 17, 47–62.
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.
Fatica, A.; Bozzoni, I. Long non-coding RNAs: New players in cell differentiation and development. Nat. Rev. Genet. 2014, 15, 7–21.
Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 2012, 338, 1435–1439.
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.
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.
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.
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 radiation- based techniques. Biomaterials 2014, 35, 6412–6421.
Sun, M.; Zhang, G.; Liu, H. J.; Liu, Y.; Li, J. H. α- and γ-Fe2O3 nanoparticle/nitrogen doped carbon nanotube catalysts for high-performance oxygen reduction reaction. Sci. China Mater. 2015, 58, 683–692.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Wu, M. R.; Chen, G. Q.; Li, Y.-P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016, 4, 16009.
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.
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.
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.
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.
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.
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.
Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J. 2003, 22, 2443–2452.
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.
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.
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.
Kirschvink, J. L.; Walker, M. M.; Diebel, C. E. Magnetite- based magnetoreception. Curr. Opin. Neurobiol. 2001, 11, 462–467.
Winklhofer, M.; Kirschvink, J. L. A quantitative assessment of torque-transducer models for magnetoreception. J. R. Soc. Interface 2010, 7, S273–S289.
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.
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.
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.
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.
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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).
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