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Nanotechnology to Drive Stem Cell Commitment

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Nanotechnology to Drive Stem Cell Commitment REVIEW Nanotechnology to drive stem cell commitment Stem cells (SCs) are undifferentiated cells responsible for the growth, homeostasis and repair of many tissues. The maintenance and survival of SCs is strongly influenced by several stimuli from the local microenvironment. The majority of signaling molecules interact with SCs at the nanoscale level. Therefore, scaffolds with surface nanostructures have potential applications for SCs and in the field of regenerative medicine. Although some strategies have already reached the field of cell biology, strategies based on modification at nanoscale level are new players in the fields of SCs and tissue regeneration. The introduction of the possibility to perform such modifications to these fields is probably due to increasing improvements in nanomaterials for biomedical applications, as well as new insights into SC biology. The aim of the present review is to exhibit the most recent applications of nanostructured materials that drive the commitment of adult SCs for potential clinical applications. 1,2 KEYWORDS: adipogenesis n adipose-derived stem cells n adult stem cells Eriberto Bressan , n differentiation n mesenchymal stem cell n nanoparticles n nanotechnology Amedeo Carraro3, Letizia n nanotubes n neurogenesis n osteogenesis Ferroni4, Chiara Gardin4, Luca Sbricoli1, Riccardo Nanotechnology represents a fascinating new SCs and are responsible for the generation of Guazzo1, Edoardo outlook on regenerative medicine that could cells with different properties. These cells can Stellini1, Marco Roman5, promote extensive research and lead to the either multiply (progenitors or transit amplify- Paolo Pinton2, Stefano realization of interesting and innovative tools ing cells) or be committed to terminal differ- Sivolella1,2 & Barbara [1,2] to improve and restore tissue function . entiation. Progenitors and transit amplifying 4 Worldwide interest in both adult stem cells cells have a limited lifespan and, therefore, can Zavan* (SCs) and embryonic SCs in the fields of tis- only reconstitute a tissue for a short period of 1Department of Neurosciences, University of Padova, Via Venezia 90, sue engineering and regenerative medicine has time when transplanted. By contrast, SCs are 35100 Padova, Italy 2 grown tremendously in recent years [3,4]. SCs self-renewing and, therefore, can generate any Department of Experimental & Diagnostic Medicine, Section of have been identified as having the potential tissue for a lifetime. This is a key property for a General Pathology, Interdisciplinary capacity to replace cells that are damaged or successful therapy. The capacity to expand SCs Center for the Study of Inflammation (ICSI) and LTTA Center, University of diseased and to restore vital functions, mak- in culture is an indispensable step for regen- Ferrara, Ferrara 44100, Italy ing them key players in tissue regeneration. erative medicine, and a considerable effort has 31st General Surgery, Department of Furthermore, the decreased immunogenicity been made to evaluate the consequences of General Surgery & Odontoiatrics, University Hospital of Verona, P.le A. and potential ‘immunomodulatory’ properties the cultivation on SC behavior [8]. Classically, Stefani 1, 37126, Verona, Italy that have been observed in various populations the control of SC fate either in vivo or in vitro 4Department of Biomedical Sciences, University of Padova, Via G. Colombo 3, of adult SCs may also facilitate allogenic trans- has been attributed to genetic and molecular 35100 Padova, Italy plantation, providing advantageous sources for mediators (e.g., growth factors or transcrip- 5IDPA-CNR, Institute for the Dynamics of Environmental Processes, Calle cell-based therapies [3–5]. Recent insights into tion factors). However, increasing evidence Author ProofLarga S. Marta 2137, 30123, Venice, the multilineage potential and inherited plastic- has revealed that a different array of additional Italy ity of progenitor cells have also created oppor- environmental factors, which belong to the *Author for correspondence: Tel.: +39 827 6096 tunities, dictated by an increased need for new ‘nanodimension’, may contribute to the overall Fax: +39 827 6079 cell-based therapies, to enable the regulation control of the activity of SCs; this may herald [email protected] of cell growth, differentiation and phenotypic the advent of new perspectives in biomedical expression through the modulation of SCs [6,7]. research [9–11] . The integration of nanotechno- A SC is defined as a cell that can continuously logical biomimetic materials and translational produce unaltered daughters and, furthermore, medicine could provide the chance to produce has the ability to generate cells with different surfaces (e.g., bone, vasculature, heart tissue, and more restricted properties. SCs can divide cartilage, bladder tissue and brain tissue), struc- either symmetrically (allowing an increase in tures and systems with nanoscale features that SC number) or asymmetrically. Asymmetric can mimic the natural cellular environment divisions maintain the number of unaltered and quickly promote cellular events, such as part of 10.2217/NNM.13.12 © 2013 Future Medicine Ltd Nanomedicine (2013) 8(3), 1–18 ISSN 1743-5889 1 REVIEW Bressan, Carraro, Ferroni et al. Nanotechnology to drive stem cell commitment REVIEW adhesion, mobility and differentiation [12–14]. recruit numerous proteins such as FAK, vincu- Further improvements, stemming from the lin, paxillin, talin and p130Cas, among others optimization of nanomaterials by the continu- [18]. The process of this concentration and the ous introduction of nanotechnology platforms, topography of cell-adhesion sites in the ECM will boost the development of innovative cell- are critical to integrin clustering and activation based therapeutics. The aim of this review is to (FIGURES 2 & 3). For this reason, parameters includ- evaluate the current strategies and the emerging ing size, lateral spacing, surface chemistry and applications of nanotechnology and its goals in the geometry of nanofeatures are important SC and regenerative medicine research. variables that guide SC behavior [19–21] . Moreover, Seo et al. demonstrated, after cul- Commitment by nanopatterned turing bone marrow murine mesenchymal SCs substrates (MSCs) on both flat and microscale or nanoscale nExtracellular environment & cell patterned topographies, that the formation and adhesion maturation of FAs is highly dependent on the The selection of a good-quality scaffold is an topography of the substrate, while the shape, essential strategy for tissue engineering. Ideally, morphology and spreading of cells on different the scaffold should be a functional and structural substrates were not significantly different[22] . platform able to mimic the native extracellular The preconditioning of cellular function at matrix (ECM) and support the morphogenesis nanostructured interfaces may result from direct of multiple tissues; on this basis, 3D nanofi- influence on cellular responses or an altered brous scaffolds appear to be the most capable of ECM layer deposited on the surface and a con- influencing cellular behavior. Nanotechnology, sequent change in the availability of binding as defined by the US National Nanotechnology sites [23,24]. Initiative (US NNI 2010), involves “structures With the inherent plasticity and multilineage with dimensions between approximately 1 and potential provided by SCs comes an increased 100 nanometers.” We can assume that all stud- need for regulating cell differentiation, growth ies focused on the interactions between cells and phenotypic expression. Classically, the con- and nanoscale materials are nanotechnology, trol of SC fate, either in vivo or in vitro, has been and their further in vivo applications can be attributed principally to genetic and molecular consequently called nanomedicine [15] . mediators (e.g., growth factors and transcrip- The interactions between cells and ECM tion factors). However, increasing evidence components strongly influence cell growth, has revealed that a diverse array of additional guide cell mobility and differentiation, and environmental factors contribute to the overall affect general cellular behavior; as a conse- control of SC activity. In particular, fascinating quence, cell–substratum interaction maintains data continue to mount on the important influ- a central role in many biological phenomena ence of the ‘solid-state’ environment, in other (FIGURE 1). Knowledge of these interactions is cru- words, the influence ECM has on SC fate, with cial to the understanding of many fundamental particular emphasis on the interactions of ECM biological questions and to the design of medical ligands with cell surface receptors [25]. However, devices. The complex structures of soluble and it is now clear that ECM-based control of the immobilized biomacromolecules in the ECM, cell may also occur through multiple physical including collagens, glycoproteins and glyco- mechanisms, such as ECM geometry at the Authorsaminoglycans, range from several to hundreds Proof microscale and nanoscale, and ECM elastic- of nanometers in size. For example, collagens ity or mechanical signals transmitted from the have a hierarchical structure composed of fibrils ECM to the cells. In addition to the influence ranging from 10 to 300 nm in size to collagen that an artificial ECM may have on cell shape, fibers that can be up to several microns in size. there is significant evidence that other physical At the other end of the spectrum,
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