Behaviors of stem cells on carbon nanotube
© Lee et al.; licensee BioMed Central. 2015
Received: 30 July 2014
Accepted: 11 December 2014
Published: 2 February 2015
Regulating stem cell microenvironment is one of the essential elements in stem cell culture. Recently, carbon nanotube (CNT) has come into the spotlight as a biomaterial that retains unique properties. Based on its high chemical stability, elasticity, mechanical strength, and electrical conductivity, CNT shows great potential as an application for biomedical substrate. Also, properties of CNT could be further regulated by appropriate chemical modifications of CNT. Recent studies reported that modulating the cellular microenvironment through the use of CNT and chemically modified CNT as cell culture substrates can affect proliferation and differentiation of various types of stem cells. This review summarizes the unique biological effects of CNT on stem cells.
KeywordsCarbon nanotube Differentiation Stem cell Substrate
Stem cells, which have the ability to self-renew and multipotently differentiate into several phenotypes, have been regarded critical for groundbreaking therapy in the field of regenerative medicine. Therefore, strategies to promote their proliferation and control their differentiation are subject of great interest. In tissue engineering, mesenchymal stem cells (MSCs), neural stem cells (NSCs), and embryonic stem cells (ESCs) can be induced to differentiate into various terminally differentiated cells including chondrocytes, osteoblasts, neurons, and myocytes under specific culture conditions. These differentiated cells can be injected directly into damaged tissue or conjugated with specific substrates, and used to regenerate damaged tissues. MSCs, NSCs, and ESCs can be differentiated into mature cells by modulating their cellular microenvironment. One of the most effective ways to control the fate of stem cells is by changing the properties of the cell culture substrates, which can provide dynamic microenvironmental and morphological cues for stem cell proliferation and differentiation. CNT has emerged as a new potential cellular culture substrate that could alter the behavior of stem cells .
This review briefly outlines the unique characteristics of CNT and highlights the recent applications of CNT for tissue engineering through stem cell differentiation. Also, biocompatibility and toxicity of CNT will be discussed in this review.
Stem cell differentiation on carbon nanotube
Stem cells play an important role in tissue engineering and regenerative medicine because of their ability to self-renew and differentiate. Controlling the fate of stem cells is one of the most studied issues in tissue engineering. As a culture substrate, CNT has drawn tremendous interests in tissue engineering as it has the ability to dynamically direct stem cells lineage. For example, CNT has a high binding affinity to biological molecules such as extracellular matrix (ECM) proteins. Due to its high binding affinity to ECM proteins such as fibronectin, CNT can efficiently control cellular behavior . In addition, as mentioned above, properties of CNT can be easily modified to improve its biocompatibility as a cellular culture substrate. So far, CNT has been a subject of studies for culture of various stem cell lines, such as neural stem cells, embryonic stem cells, and mesenchymal stem cells.
Neural stem cells
Embryonic stem cells
Not only CNT imposes great effects on neuronal differentiation of NSCs, but also it has been reported to promote neural differention of human ESCs (hESCs). When hESCs were seeded onto hydrophilic CNT-poly(acrylic acid) composite, hESCs differentiation toward neuronal lineages was elevated up to two-fold when compared to the hESCs cultured with poly(L-ornithine) (PLO), the conventional standard polymer for culturing neural cells. Moreover, the substrate composite showed no effect on hESCs viability and adhesion . In addition, CNT/collagen composite was reported to promote neural differentiation of hESCs. Type I collagen, which is one of the major component of ECMs that support neuronal cell types, was modified with CNT. Not only CNT improved the biocompatibility of the collagen, but also it heightened the interaction between the collagen compound hESCs cultured on this CNT/collagen composite differentiated into ectodermal lineage in day 3, and into neural lineage in day 6, with enhanced expression of nestin . Nestin is a representative marker that identifies neural stem cells . Also, poly(methacrylic acid)-grafted CNT can greatly enhanced the differentiation of hESCs into neural lineage compared to the hESCs cultured on PLO substrate .
Mesenchymal stem cells
Biocompatibility and toxicity
Developing a biocompatible and nontoxic substrate that can facilitate stem cells proliferation and differentiation is one of the most pivotal subjects in stem cell research. Pristine CNT shows poor dispersion within most types of solvents. It is insoluble and chemically inert in culture media. CNT alone is rarely used in medical applications, as insoluble CNT among cells can be toxic to the cells . Therefore, surface modification of the CNT is necessary. CNT that has undergone surface modifications could allow higher activity and interaction between the CNT and the cell. In addition, one of the main concerns about CNT composite application on tissue engineering is the harmful immune response against CNT. Coating CNT with biocompatible protein has been the candidate to alleviate the immune response. For example, laminin, an essential part of human ECM, was fabricated with SWCNTs in layer-by-layer structure. SWCNT-laminin films eventually minimized the immune response without affecting neural differentiation potential of CNT. The result implied that CNT-protein composite can be used as a potential biocompatible material for neural tissue engineering .
Potential toxicity of CNT has been a considerably important issue for biomedical applications. CNT toxicity depends on its physical and chemical properties, such as CNT dimensional parameter or nature of the attaching target surface. However, there are still no general theories on what makes CNT more or less biocompatible and toxic. Despite numerous studies, it is uncertain to either classify CNT as a toxic or nontoxic material. Although CNT shows toxicity at some degree, it could be mitigated by controlling some of its properties. With sustained research, CNT could be hope for a potential biomedical tool.
CNT has emerged as a promising biocompatible substrate among researchers for its unique properties. In tissue engineering, it is important for the substrate to mimic the natural environment of stem cells in order to control direction, proliferation, and differentiation of stem cells. In nature, both proliferation and differentiation of stem cells are highly related to external signals and metabolic pathways those are dependent on the ECM. In other words, proliferation and differentiation of stem cells are favorably based on the nanotopography and microenvironment of cell adhesion substrates. CNT could be managed to represent a favorable topography and microenvironment for stem cells. However, there are still various technical shortages that should be investigated for CNT application on cell therapy. The future potential of CNT application is promising for broad types of tissue therapies such as heart, liver, bone, and other tissues.
Mesenchymal stem cell
Neural stem cell
Embryonic stem cell
Single-walled carbon nanotube
Multi-walled carbon nanotube
Carboxylic functionalized carbon nanotube
Microtubule-associated protein 2
Human embryonic stem cell
Human mesenchymal stem cell
Glial fibrillary acid protein
This research was supported by a grant (2014029716) from the National Research Foundation of Korea and a grant (HI12C0199) from the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea.
- Hazeltine LB, Selekman JA, Palecek SP: Engineering the human pluripotent stem cell microenvironment to direct cell fate. Biotechnol Adv 2013, 31:1002–1019.View ArticleGoogle Scholar
- Iijima S, Ajayan PM, Ichihashi T: Growth model for carbon nanotubes. Phys Rev Lett 1992, 69:3100–3103.View ArticleGoogle Scholar
- Hummer G, Rasaiah JC, Noworyta JP: Water conduction through the hydrophobic channel of a carbon nanotube. Nature 2001, 414:188–190.View ArticleGoogle Scholar
- Zhang Q, Huang JQ, Zhao MQ, Qian WZ, Wei F: Carbon nanotube mass production: principles and processes. ChemSusChem 2011, 4:864–889.View ArticleGoogle Scholar
- Fischer JE: Chemical doping of single-wall carbon nanotubes. Accounts Chem Res 2002, 35:1079–1086.View ArticleGoogle Scholar
- Tasis D, Tagmatarchis N, Bianco A, Prato M: Chemistry of carbon nanotubes. Chem Rev 2006, 106:1105–1136.View ArticleGoogle Scholar
- Moore VC, Strano MS, Haroz EH, Hauge RH, Smalley RE, Schmidt J, Talmon Y: Individually suspended single-walled carbon nanotubes in various surfactants. Nano Lett 2003, 3:1379–1382.View ArticleGoogle Scholar
- Dieckmann GR, Dalton AB, Johnson PA, Razal J, Chen J, Giordano GM, Munoz E, Musselman IH, Baughman RH, Draper RK: Controlled assembly of carbon nanotubes by designed amphiphilic peptide helices. J Am Chem Soc 2003, 125:1770–1777.View ArticleGoogle Scholar
- Zheng M, Jagota A, Semke ED, Diner BA, Mclean RS, Lustig SR, Richardson RE, Tassi NG: DNA-assisted dispersion and separation of carbon nanotubes. Nat Mater 2003, 2:338–342.View ArticleGoogle Scholar
- MacDonald RA, Laurenzi BF, Viswanathan G, Ajayan PM, Stegemann JP: Collagen-carbon nanotube composite materials as scaffolds in tissue engineering. J Biomed Mater Res A 2005, 74:489–496.View ArticleGoogle Scholar
- Cheng HKF, Basu T, Sahoo NG, Li L, Chans SH: Current advances in the carbon nanotube/thermotropic main-chain liquid crystalline polymer nanocomposites and their blends. Polymers 2012, 4:889–912.View ArticleGoogle Scholar
- Fabbro A, Prato M, Ballerini L: Carbon nanotubes in neuroregeneration and repair. Adv Drug Deliv Rev 2013, 65:2034–2044.View ArticleGoogle Scholar
- Bates K, Kostarelos K: Carbon nanotubes as vectors for gene therapy: past achievements, present challenges and future goals. Adv Drug Dliv Rev 2013, 65:2023–2033.View ArticleGoogle Scholar
- Meredith JR, Jin C, Narayan RJ, Aggarwal R: Biomedical applications of carbon-nanotube composites. Front Biosci 2012, 5:610–621.Google Scholar
- Namgung S, Kim T, Baik KY, Lee M, Nam JM, Hong S: Fibronectin-Carbon-Nanotube Hybrid Nanostructures for Controlled Cell Growth. Small 2011, 7:56–61.View ArticleGoogle Scholar
- Mazzatenta A, Giugliano M, Campidelli S, Gambazzi L, Businaro L, Markram H, Prato M, Ballerini L: Interfacing neurons with carbon nanotubes: Electrical signal transfer and synaptic stimulation in cultured brain circuits. J Neurosci 2007, 27:6931–6936.View ArticleGoogle Scholar
- Jan E, Kotov NA: Successful differentiation of mouse neural stem cells on layer-by-layer assembled single-walled carbon nanotube composite. Nano Lett 2007, 7:1123–1128.View ArticleGoogle Scholar
- Dowell-Mesfin NM, Abdul-Karim MA, Turner AMP, Schanz S, Craighead HG, Roysam B, Turner JN, Shain W: Topographically modified surfaces affect orientation and growth of hippocampal neurons. J Neural Eng 2004, 1:78–90.View ArticleGoogle Scholar
- Hu H, Ni Y, Montana V, Haddon RC, Parpura V: Chemically functionalized carbon nanotubes as substrates for neuronal growth. Nano Lett 2004, 4:507–511.View ArticleGoogle Scholar
- Kam NW, Jan E, Kotov NA: Electrical stimulation of neural stem cells mediated by humanized carbon nanotube composite made with extracellular matrix protein. Nano Lett 2009, 9:273–278.View ArticleGoogle Scholar
- Park SY, Choi DS, Jin HJ, Park J, Byun KE, Lee KB, Hong S: Polarization-Controlled Differentiation of Human Neural Stem Cells Using Synergistic Cues from the Patterns of Carbon Nanotube Monolayer Coating. Acs Nano 2011, 5:4704–4711.View ArticleGoogle Scholar
- Chao TI, Xiang SH, Chen CS, Chin WC, Nelson AJ, Wang CC, Lu J: Carbon nanotubes promote neuron differentiation from human embryonic stem cells. Biochem Bioph Res Co 2009, 384:426–430.View ArticleGoogle Scholar
- Sridharan I, Kim T, Wang R: Adapting collagen/CNT matrix in directing hESC differentiation. Biochem Bioph Res Co 2009, 381:508–512.View ArticleGoogle Scholar
- Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B, Mann J, Vassileva G, McMahon A: Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 1994, 12:11–24.View ArticleGoogle Scholar
- Chao TI, Xiang S, Lipstate JF, Wang C, Lu J: Poly(methacrylic acid)-grafted carbon nanotube scaffolds enhance differentiation of hESCs into neuronal cells. Adv Mater 2010, 22:3542–3547.View ArticleGoogle Scholar
- Tay CY, Gu HG, Leong WS, Yu HY, Li HQ, Heng BC, Tantang H, Loo SCJ, Li LJ, Tan LP: Cellular behavior of human mesenchymal stem cells cultured on single-walled carbon nanotube film. Carbon 2010, 48:1095–1104.View ArticleGoogle Scholar
- Johnson GVW, Jope RS: The Role of Microtubule-Associated Protein-2 (Map-2) in Neuronal Growth, Plasticity, and Degeneration. J Neurosci Res 1992, 33:505–512.View ArticleGoogle Scholar
- Namgung S, Baik KY, Park J, Hong S: Controlling the growth and differentiation of human mesenchymal stem cells by the arrangement of individual carbon nanotubes. Acs Nano 2011, 5:7383–7390.View ArticleGoogle Scholar
- Baik KY, Park SY, Heo K, Lee KB, Hong S: Carbon Nanotube Monolayer Cues for Osteogenesis of Mesenchymal Stem Cells. Small 2011, 7:741–745.View ArticleGoogle Scholar
- Mooney E, Mackle JN, Blond DJ, O'Cearbhaill E, Shaw G, Blau WJ, Barry FP, Barron V, Murphy JM: The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs. Biomaterials 2012, 33:6132–6139.View ArticleGoogle Scholar
- Zhu L, Chang DW, Dai LM, Hong YL: DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano Lett 2007, 7:3592–3597.View ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.