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• W2000703762 abstract "Nanotechnologies are emerging platforms that could be useful in measuring, understanding, and manipulating stem cells. Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking; nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotides and protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation and transplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation, and transplantation. We further discuss their utility and the potential concerns regarding their cytotoxicity. Nanotechnologies are emerging platforms that could be useful in measuring, understanding, and manipulating stem cells. Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking; nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotides and protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation and transplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation, and transplantation. We further discuss their utility and the potential concerns regarding their cytotoxicity. The wide spectrum of nanotechnologies (referred to as nanomedicine by the National Institutes of Health for applications in the biomedical area) holds great promise for the study of stem cell biology and the development of new approaches to stem cell expansion, differentiation, and transplantation (Chen et al., 2007Chen H. Titushkin I. Stroscio M. Cho M. Altered membrane dynamics of quantum dot-conjugated integrins during osteogenic differentiation of human bone marrow derived progenitor cells.Biophys. J. 2007; 92: 1399-1408Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, Silva et al., 2004Silva G.A. Czeisler C. Niece K.L. Beniash E. Harrington D.A. Kessler J.A. Stupp S.I. Selective differentiation of neural progenitor cells by high-epitope density nanofibers.Science. 2004; 303: 1352-1355Crossref PubMed Scopus (1830) Google Scholar, Sniadecki et al., 2006Sniadecki N.J. Desai R.A. Ruiz S.A. Chen C.S. Nanotechnology for cell-substrate interactions.Ann. Biomed. Eng. 2006; 34: 59-74Crossref PubMed Scopus (285) Google Scholar). The term “nanotechnologies” in the title of this article reflects nanoscale (on the scale of approximately 1–1000 nm) or nanostructured materials used for medical diagnosis, drug delivery, and implants, which require novel and demanding chemical and manufacturing techniques. Therefore, the concept implies either the improvement of current materials or the advent of new materials with modified fundamental properties and bioactivity. Examples of nanotechnologies in stem cell research are organic and inorganic nanoparticles (Corsi et al., 2003Corsi K. Chellat F. Yahia L. Fernandes J.C. Mesenchymal stem cells, MG63 and HEK293 transfection using chitosan-DNA nanoparticles.Biomaterials. 2003; 24: 1255-1264Crossref PubMed Scopus (333) Google Scholar, Huang et al., 2005Huang D.M. Hung Y. Ko B.S. Hsu S.C. Chen W.H. Chien C.L. Tsai C.P. Kuo C.T. Kang J.C. Yang C.S. et al.Highly efficient cellular labeling of mesoporous nanoparticles in human mesenchymal stem cells: implication for stem cell tracking.FASEB J. 2005; 19: 2014-2016Crossref PubMed Scopus (43) Google Scholar, Kutsuzawa et al., 2008Kutsuzawa K. Akaike T. Chowdhury E.H. The influence of the cell-adhesive proteins E-cadherin and fibronectin embedded in carbonate-apatite DNA carrier on transgene delivery and expression in a mouse embryonic stem cell line.Biomaterials. 2008; 29: 370-376Crossref PubMed Scopus (28) Google Scholar), quantum dots (Chen et al., 2007Chen H. Titushkin I. Stroscio M. Cho M. Altered membrane dynamics of quantum dot-conjugated integrins during osteogenic differentiation of human bone marrow derived progenitor cells.Biophys. J. 2007; 92: 1399-1408Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, Shah et al., 2007Shah B.S. Clark P.A. Moioli E.K. Stroscio M.A. Mao J.J. Labeling of mesenchymal stem cells by bioconjugated quantum dots.Nano Lett. 2007; 7: 3071-3079Crossref PubMed Scopus (129) Google Scholar, Slotkin et al., 2007Slotkin J.R. Chakrabarti L. Dai H.N. Carney R.S. Hirata T. Bregman B.S. Gallicano G.I. Corbin J.G. Haydar T.F. In vivo quantum dot labeling of mammalian stem and progenitor cells.Dev. Dyn. 2007; 236: 3393-3401Crossref PubMed Scopus (88) Google Scholar), carbon nanotubes (Zhu et al., 2007Zhu L. Chang D.W. Dai L. Hong Y. DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells.Nano Lett. 2007; 7: 3592-3597Crossref PubMed Scopus (305) Google Scholar), nanofibers (Dang and Leong, 2007Dang J. Leong K. Myogenic induction of aligned mesenchymal stem cells by culture on thermally responsive electrospun nanofibers.Adv. Mater. 2007; 19: 2775-2779Crossref PubMed Scopus (166) Google Scholar, Silva et al., 2004Silva G.A. Czeisler C. Niece K.L. Beniash E. Harrington D.A. Kessler J.A. Stupp S.I. Selective differentiation of neural progenitor cells by high-epitope density nanofibers.Science. 2004; 303: 1352-1355Crossref PubMed Scopus (1830) Google Scholar, Yang et al., 2005Yang F. Murugan R. Wang S. Ramakrishna S. Electrospinning of nano/micro scale poly(L-lactic acid) aligned fibers and their potential in neural tissue engineering.Biomaterials. 2005; 26: 2603-2610Crossref PubMed Scopus (1483) Google Scholar), and nanoscale-engineered substrates (Bettinger et al., 2008Bettinger C.J. Zhang Z. Gerecht S. Borenstein J.T. Langer R. Enhancement of in vitro capillary tube formation by substrate nanotopography.Adv. Mater. 2008; 20: 99-103Crossref PubMed Scopus (141) Google Scholar, Dalby et al., 2007Dalby M.J. Gadegaard N. Tare R. Andar A. Riehle M.O. Herzyk P. Wilkinson C.D. Oreffo R.O. The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder.Nat. Mater. 2007; 6: 997-1003Crossref PubMed Scopus (1843) Google Scholar, Derda et al., 2007Derda R. Li L. Orner B.P. Lewis R.L. Thomson J.A. Kiessling L.L. Defined substrates for human embryonic stem cell growth identified from surface arrays.ACS Chem. Biol. 2007; 2: 347-355Crossref PubMed Scopus (115) Google Scholar, Jan and Kotov, 2007Jan E. Kotov N.A. Successful differentiation of mouse neural stem cells on layer-by-layer assembled single-walled carbon nanotube composite.Nano Lett. 2007; 7: 1123-1128Crossref PubMed Scopus (269) Google Scholar) (Figure 1). Potential applications of nanotechnologies in stem cell research include (1) tracking of stem cell surface molecules and detailed examination of molecular motion without photobleaching, (2) noninvasive tracking of stem cells and progenitor cells transplanted in vivo, (3) stem cell delivery systems that enhance the survival of transplanted cells by releasing prosurvival biomolecules, (4) nanopatterned substrates that present covalently tethered biologically active molecules (adhesion sites, growth factors, and synthetic peptides) for stem cell differentiation and transplantation, and (5) intracellular delivery of DNA, RNAi, proteins, peptides, and small drugs for stem cell differentiation (Moghimi et al., 2005Moghimi S.M. Hunter A.C. Murray J.C. Nanomedicine: current status and future prospects.FASEB J. 2005; 19: 311-330Crossref PubMed Scopus (1499) Google Scholar, Muschler et al., 2004Muschler G.F. Nakamoto C. Griffith L.G. Engineering principles of clinical cell-based tissue engineering.J. Bone Joint Surg. Am. 2004; 86-A: 1541-1558PubMed Google Scholar). Though nanotechnologies are very powerful with respect to micro- and macroenvironmental control, they may have harmful drawbacks. Systematic studies must assess their toxicological profiles and evaluate potential interference with the self-renewal and differentiation programs of stem cells. Although some of the nanotechnologies described herein have already been applied to cell biology, their use in stem cell biology and regenerative medicine is more recent. This is likely due to (1) advances in the preparation of safer and more effective nanomaterials for biomedical applications, (2) growing awareness of material science and tissue engineering researchers regarding the potential of stem cells for regenerative medicine, (3) notable success in the application of nanotechnologies to medicine, and (4) developments in stem cell biology and the isolation of novel sources of stem cells. Recent developments in the use of nanotechnologies with stem cells have been motivated by the continuous introduction of novel nanotechnology platforms during the last few years. Some of the nanomaterials reviewed here were discovered in the 1990s through technological developments such as carbon nanotubes, quantum dots, and nanowires. In some cases, the use of nanotechnologies in the stem cell field was propelled by research performed initially on somatic cells. For example, although the use of quantum dots for cell labeling was described in 1998 (Bruchez et al., 1998Bruchez Jr., M. Moronne M. Gin P. Weiss S. Alivisatos A.P. Semiconductor nanocrystals as fluorescent biological labels.Science. 1998; 281: 2013-2016Crossref PubMed Scopus (8012) Google Scholar, Chan and Nie, 1998Chan W.C. Nie S. Quantum dot bioconjugates for ultrasensitive nonisotopic detection.Science. 1998; 281: 2016-2018Crossref PubMed Scopus (6898) Google Scholar), their use for labeling stem cells is recent (Hsieh et al., 2006bHsieh S.C. Wang F.F. Lin C.S. Chen Y.J. Hung S.C. Wang Y.J. The inhibition of osteogenesis with human bone marrow mesenchymal stem cells by CdSe/ZnS quantum dot labels.Biomaterials. 2006; 27: 1656-1664Crossref PubMed Scopus (103) Google Scholar, Seleverstov et al., 2006Seleverstov O. Zabirnyk O. Zscharnack M. Bulavina L. Nowicki M. Heinrich J.M. Yezhelyev M. Emmrich F. O'Regan R. Bader A. Quantum dots for human mesenchymal stem cells labeling. A size-dependent autophagy activation.Nano Lett. 2006; 6: 2826-2832Crossref PubMed Scopus (223) Google Scholar). Similarly, though the use of magnetic nanoparticles for intracellular labeling and detection by MRI was reported in the early 1990s (Yeh et al., 1993Yeh T.C. Zhang W. Ildstad S.T. Ho C. Intracellular labeling of T-cells with superparamagnetic contrast agents.Magn. Reson. Med. 1993; 30: 617-625Crossref PubMed Scopus (178) Google Scholar), only in 2000 were they applied to stem and progenitor cells (Lewin et al., 2000Lewin M. Carlesso N. Tung C.H. Tang X.W. Cory D. Scadden D.T. Weissleder R. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.Nat. Biotechnol. 2000; 18: 410-414Crossref PubMed Scopus (1584) Google Scholar). In other cases, some established nanotechnologies were only recently used in the biomedical arena. The first patent in the preparation of electrospun nanofibers was awarded in 1934; however, they received little interest from biomedical researchers until the mid 1990s (Dzenis, 2004Dzenis Y. Material science. Spinning continuous fibers for nanotechnology.Science. 2004; 304: 1917-1919Crossref PubMed Scopus (1000) Google Scholar), and only in the 21st century were nanoscaffolds prepared for the culture and transplantation of stem cells (Li et al., 2005Li W.J. Tuli R. Okafor C. Derfoul A. Danielson K.G. Hall D.J. Tuan R.S. A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells.Biomaterials. 2005; 26: 599-609Crossref PubMed Scopus (806) Google Scholar). As necessity is often considered the mother of invention, new techniques are adapted when the need is recognized as a general problem. For example, as exogenous cell therapy undergoes rigorous testing in animal and human trials, it has become increasingly important to track the movement of transplanted cells to assess toxicity and therapeutic efficacy. The history and fate of transplanted stem cells or progenitor cells is generally assessed by labeling them in vitro with a fluorescent dye, thymidine analog (e.g., BrdU), or a transfected gene such as LacZ or green fluorescent protein (GFP) and visualization by immunohistochemistry after the removal of tissues or organs. One of the main goals in stem cell research is long-term noninvasive imaging of transplanted cells in vivo to monitor their survival, migration, differentiation, and regenerative impact. Magnetic resonance imaging (MRI) provides a noninvasive, in vivo method for studying the fate of transplanted cells labeled with magnetic nanoparticles. MRI offers several advantages over other techniques such as positron emission tomography including greater speed, higher spatial resolution, more direct anatomical correlation, and lower cost (Stroh et al., 2005Stroh A. Faber C. Neuberger T. Lorenz P. Sieland K. Jakob P.M. Webb A. Pilgrimm H. Schober R. Pohl E.E. Zimmer C. In vivo detection limits of magnetically labeled embryonic stem cells in the rat brain using high-field (17.6 T) magnetic resonance imaging.Neuroimage. 2005; 24: 635-645Crossref PubMed Scopus (95) Google Scholar). In vivo images with a spatial resolution of 50 × 50 × 500 μm can be acquired over 2 to 3 hr (Allport and Weissleder, 2001Allport J.R. Weissleder R. In vivo imaging of gene and cell therapies.Exp. Hematol. 2001; 29: 1237-1246Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Superparamagnetic iron oxide (SPIO) nanoparticles have been used as a feasible means to enhance the contrast of cellular targets in MRI. Among several types of nanoparticles described, some (e.g., Feridex/Endorem and Ferucarbotran) have been approved for human use by the U.S. Food and Drug Administration (FDA) as MRI contrast agents (Reimer and Balzer, 2003Reimer P. Balzer T. Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications.Eur. Radiol. 2003; 13: 1266-1276PubMed Google Scholar, Wang et al., 2001Wang Y.X. Hussain S.M. Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging.Eur. Radiol. 2001; 11: 2319-2331Crossref PubMed Scopus (1137) Google Scholar) (Table S1 available online). Generally, a SPIO nanoparticle is composed of an iron oxide core coated with dextran (ferumoxides, commercialized by Guerbert and Berlex Laboratories under the trademarks Endorem and Feridex, respectively) or carboxydextran (Ferucarbotran, commercialized by Schering) that ensures aqueous solubility and prevents nanoparticle aggregation (Reimer and Balzer, 2003Reimer P. Balzer T. Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications.Eur. Radiol. 2003; 13: 1266-1276PubMed Google Scholar, Wang et al., 2001Wang Y.X. Hussain S.M. Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging.Eur. Radiol. 2001; 11: 2319-2331Crossref PubMed Scopus (1137) Google Scholar). The iron oxide core is normally formed by magnetite Fe3O4. The overall hydrodynamic diameters of Ferucarbotran and Feridex/Endorem are 80–150 nm and 62 nm, respectively (Wang et al., 2001Wang Y.X. Hussain S.M. Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging.Eur. Radiol. 2001; 11: 2319-2331Crossref PubMed Scopus (1137) Google Scholar). Most labeling techniques currently use one of two approaches: (1) attaching magnetic nanoparticles to the stem cell surface or (2) internalizing biocompatible magnetic nanoparticles by endocytosis or phagocytosis. Surface labeling has some limitations, including iron content that is generally lower by an order of magnitude than intracellular labeling procedures using SPIO nanoparticles (Sykova and Jendelova, 2005Sykova E. Jendelova P. Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord.Ann. N Y Acad. Sci. 2005; 1049: 146-160Crossref PubMed Scopus (127) Google Scholar). In addition, although surface labeling is efficient for in vitro cell separation, it is generally unsuitable for in vivo use because of rapid reticuloendothelial recognition and clearance of labeled cells (Lewin et al., 2000Lewin M. Carlesso N. Tung C.H. Tang X.W. Cory D. Scadden D.T. Weissleder R. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.Nat. Biotechnol. 2000; 18: 410-414Crossref PubMed Scopus (1584) Google Scholar). For in vivo tracking using magnetic resonance cell imaging, SPIO nanoparticles are generally taken up through stem cell endocytosis during in vitro cultivation (Figure 2). Human mesenchymal stem cells (hMSCs) internalize SPIO nanoparticles in the absence of transfection agents at a concentration up to 23.4 pg Fe/cell (Hsiao et al., 2007Hsiao J.K. Tai M.F. Chu H.H. Chen S.T. Li H. Lai D.M. Hsieh S.T. Wang J.L. Liu H.M. Magnetic nanoparticle labeling of mesenchymal stem cells without transfection agent: cellular behavior and capability of detection with clinical 1.5 T magnetic resonance at the single cell level.Magn. Reson. Med. 2007; 58: 717-724Crossref PubMed Scopus (99) Google Scholar). However, in most cases, internalization of SPIO nanoparticles requires the use of excipient (Table S1). For example, for improved cellular magnetic labeling, nanoparticles have been derivatized with a short HIV-1 trans-activating transcriptional activator (TAT) peptide (Lewin et al., 2000Lewin M. Carlesso N. Tung C.H. Tang X.W. Cory D. Scadden D.T. Weissleder R. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.Nat. Biotechnol. 2000; 18: 410-414Crossref PubMed Scopus (1584) Google Scholar), which mediates nanoparticle internalization by membrane receptor binding or by coating iron oxide nanoparticles with dendrimers (Bulte et al., 2001Bulte J.W. Douglas T. Witwer B. Zhang S.C. Strable E. Lewis B.K. Zywicke H. Miller B. van Gelderen P. Moskowitz B.M. et al.Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells.Nat. Biotechnol. 2001; 19: 1141-1147Crossref PubMed Scopus (952) Google Scholar). Others have used protamine sulfate, a small cationic transfection agent approved by the FDA within certain products, to facilitate the uptake of SPIO nanoparticles into stem cells (Arbab et al., 2004Arbab A.S. Yocum G.T. Kalish H. Jordan E.K. Anderson S.A. Khakoo A.Y. Read E.J. Frank J.A. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI.Blood. 2004; 104: 1217-1223Crossref PubMed Scopus (508) Google Scholar). The average iron content per cell after labeling varied from 1.47 pg to 17.90 pg Fe, depending on the incubation time, cell type, and cell culture methodology used (Arbab et al., 2004Arbab A.S. Yocum G.T. Kalish H. Jordan E.K. Anderson S.A. Khakoo A.Y. Read E.J. Frank J.A. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI.Blood. 2004; 104: 1217-1223Crossref PubMed Scopus (508) Google Scholar). Schematic representation of steps involved in cytosolic and nuclear delivery of nanomaterials into stem cells. Nanomaterials can enter the stem cell either by (i) receptor-mediated interactions or (ii) nonspecific internalization pathways. In both cases, the nanomaterials become entrapped within endosomes and are then released in the cytoplasm or trafficked to the acidic environments of lysosomes for degradation. Cytoplasm-released nanomaterials might then be transported to the nucleus of the cell. A number of factors affect the MRI detection threshold of SPIO-labeled cells, such as the SPIO concentration per cell, and intrinsic MRI parameters, such as field strength, signal-to-noise ratio, pulse sequence, and acquisition parameters (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar, Heyn et al., 2005Heyn C. Bowen C.V. Rutt B.K. Foster P.J. Detection threshold of single SPIO-labeled cells with FIESTA.Magn. Reson. Med. 2005; 53: 312-320Crossref PubMed Scopus (199) Google Scholar). Some studies have shown that as little as 1.4–3.0 pg of iron per cell is sufficient for detection with MRI (Heyn et al., 2005Heyn C. Bowen C.V. Rutt B.K. Foster P.J. Detection threshold of single SPIO-labeled cells with FIESTA.Magn. Reson. Med. 2005; 53: 312-320Crossref PubMed Scopus (199) Google Scholar). In vitro single cell detection by MRI has been described (Hoehn et al., 2002Hoehn M. Kustermann E. Blunk J. Wiedermann D. Trapp T. Wecker S. Focking M. Arnold H. Hescheler J. Fleischmann B.K. et al.Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat.Proc. Natl. Acad. Sci. USA. 2002; 99: 16267-16272Crossref PubMed Scopus (661) Google Scholar); however, in most cases MRI detection requires clusters of thousands of labeled cells (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar). SPIO-labeled stem cells/progenitor cells might contribute to our understanding of cell migration processes in the context of numerous diseases, such as neurologic diseases (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar), myocardial infarction (Arai et al., 2006Arai T. Kofidis T. Bulte J.W. de Bruin J. Venook R.D. Berry G.J. McConnell M.V. Quertermous T. Robbins R.C. Yang P.C. Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t.Magn. Reson. Med. 2006; 55: 203-209Crossref PubMed Scopus (89) Google Scholar, Kraitchman et al., 2005Kraitchman D.L. Tatsumi M. Gilson W.D. Ishimori T. Kedziorek D. Walczak P. Segars W.P. Chen H.H. Fritzges D. Izbudak I. et al.Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction.Circulation. 2005; 112: 1451-1461Crossref PubMed Scopus (453) Google Scholar), and cancer (Arbab et al., 2006Arbab A.S. Pandit S.D. Anderson S.A. Yocum G.T. Bur M. Frenkel V. Khuu H.M. Read E.J. Frank J.A. Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis.Stem Cells. 2006; 24: 671-678Crossref PubMed Scopus (141) Google Scholar). For example, magnetically labeled mouse embryonic stem cells (mESCs), injected into the nonischemic side of the brain of a rat with partial brain ischemia, migrate along the corpus callosum, populating the border zone of the ischemic area of the contralateral hemisphere (Hoehn et al., 2002Hoehn M. Kustermann E. Blunk J. Wiedermann D. Trapp T. Wecker S. Focking M. Arnold H. Hescheler J. Fleischmann B.K. et al.Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat.Proc. Natl. Acad. Sci. USA. 2002; 99: 16267-16272Crossref PubMed Scopus (661) Google Scholar). In addition, the use of SPIO-labeled stem cells in animal models of disease can help determine optimal timing and location of transplantation. A recent study has demonstrated that human central nervous system stem cells that are transplanted into a mature rodent brain migrate only after cerebral injury (cerebral stroke) (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar). In this case, stem cells transplanted into the cortical region of the brain migrate through an ipsilateral transcortical migration pathway; the extent of transcortical migration depends upon the distance between the graft site and the lesion. In addition to the information obtained from cell migration studies, SPIO technology might yield important information about the differentiation process of stem cells/progenitor cells. SPIO-labeled CD34+ progenitor cells injected into rodents can be isolated by magnetic separation after in vivo migration to study the differentiation of these cells exposed to a biological environment (Lewin et al., 2000Lewin M. Carlesso N. Tung C.H. Tang X.W. Cory D. Scadden D.T. Weissleder R. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.Nat. Biotechnol. 2000; 18: 410-414Crossref PubMed Scopus (1584) Google Scholar). A clinical study using stem cells labeled with SPIO in patients with neurological disease has recently been reported (Zhu et al., 2006Zhu J. Zhou L. XingWu F. Tracking neural stem cells in patients with brain trauma.N. Engl. J. Med. 2006; 355: 2376-2378Crossref PubMed Scopus (235) Google Scholar). This approach can be adapted to evaluate the therapeutic effects of stem cells in the context of other diseases, including myocardial infarction. SPIO nanoparticles have not been yet approved by the FDA specifically as intracellular contrast agents. The unclear framework for approving new nanomaterials as medical products (Helmus, 2007Helmus M.N. The need for rules and regulations.Nature Nanotechnology. 2007; 2: 333-334Crossref PubMed Scopus (31) Google Scholar) might delay the clinical use of SPIO nanoparticles. In clinical trials involving bone marrow-derived stem cells and hematopoietic stem cells that are used in patients within 24 hr after their isolation, the labeling of stem cells with SPIO nanoparticles should be performed in less than one day. A rapid method to label stem cells has recently been reported based in the electroporation of cells (“magnetoelectroporation”) (Walczak et al., 2005Walczak P. Kedziorek D.A. Gilad A.A. Lin S. Bulte J.W. Instant MR labeling of stem cells using magnetoelectroporation.Magn. Reson. Med. 2005; 54: 769-774Crossref PubMed Scopus (187) Google Scholar). This technique involves low-voltage pulses to induce endocytosis of contrast agents in a matter of minutes. In addition to the advantage of rapid labeling of cells, this technique does not require transfection agents for the internalization of SPIO nanoparticles, which simplifies the regulatory pathway required for approval by regulatory agencies. Despite the unique ability of MRI to track SPIO-labeled stem cells after their in vivo transplantation, this technique has some limitations. First, long-term observation of SPIO-labeled stem cells might be limited because of dilution of SPIO by cell division. For example, the initial SPIO concentration in neural stem cells (NSCs) was shown to decrease by 50% every 3 days in vitro (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar). Nonetheless, neural stem cells were tracked in vivo for up to 18 weeks (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar). Second, due to the in vivo migration of SPIO-labeled stem cells, the density of cells is reduced considerably over time, leading to a gradual loss of MRI cell signal (Guzman et al., 2007Guzman R. Uchida N. Bliss T.M. He D. Christopherson K.K. Stellwagen D. Capela A. Greve J. Malenka R.C. Moseley M.E. et al.Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI.Proc. Natl. Acad. Sci. USA. 2007; 104: 10211-10216Crossref PubMed Scopus (303) Google Scholar). Third, it is important to note that MRI cannot determine whether the SPIO-labeled stem/progenitor cells differentiate into a specific cell type, but cell function may be inferred from complementary imaging studies, such as positron emission tomography or optical imaging (Arbab et al., 2006Arbab A.S. Pandit S.D. Anderson S.A. Yocum G.T. Bur M. Frenkel V. Khuu H.M. Read E.J. Frank J.A. Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis.Stem Cells. 2006; 24: 671-678Crossref PubMed Scopus (141) Google Scholar). Fourth, in most cases, MRI studies are conducted with a 1.5 T MRI unit, which has limited spatial resolution. Improvement in spatial resolution requires stronger magnetic fields; however, the potential hazards of these magnetic fields are still unknown (Hsiao et al., 2007Hsiao J.K. Tai M.F. Chu H.H. Chen S.T. Li H. Lai D.M. Hsieh S.T. Wang J.L. Liu H.M. Magnetic nanoparticle labeling of mese" @default.
• W2000703762 created "2016-06-24" @default.
• W2000703762 creator A5022052017 @default.
• W2000703762 creator A5030531918 @default.
• W2000703762 creator A5042597057 @default.
• W2000703762 creator A5076001987 @default.
• W2000703762 date "2008-08-01" @default.
• W2000703762 modified "2023-10-18" @default.
• W2000703762 title "New Opportunities: The Use of Nanotechnologies to Manipulate and Track Stem Cells" @default.
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