In Vivo Magnetic Resonance Tracking of Magnetically Labeled Cells after Transplantation

During the last few years, the therapeutic use of stem and progenitor cells as a substitute for malfunctioning endogenous cell populations has received considerable attention. Unlike their current use in animal models, the introduction of therapeutic cells in patients will require techniques that can monitor their tissue biodistribution noninvasively. Among the different imaging modalities, magnetic resonance (MR) imaging offers both near-cellular (i.e., 25- to 50-μ) resolution and whole-body imaging capability. In order to be visualized, cells must be labeled with an intracellular tracer molecule that can be detected by MR imaging. Methods have now been developed that make it possible to incorporate sufficient amounts of superparamagnetic iron oxide into cells, enabling their detection in vivo using MR imaging. This is illustrated for (neural stem cell—derived) magnetically labeled oligodendroglial progenitors, transplanted in the central nervous system of dysmyelinated rats. Cells can be followed in vivo for at least 6 weeks after transplantation, with a good histopathologic correlation including the formation of myelin. Now that MR tracking of magnetically labeled cells appears feasible, it is anticipated that this technique may ultimately become an important tool for monitoring the efficacy of clinical (stem) cell transplantation protocols.

[1]  R. Weissleder,et al.  MRI of insulitis in autoimmune diabetes , 2002, Magnetic resonance in medicine.

[2]  J. Bulte,et al.  Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. , 2002, Academic radiology.

[3]  G. Wolswijk,et al.  Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. , 2002, Brain : a journal of neurology.

[4]  R. Rudick,et al.  Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. , 2002, The New England journal of medicine.

[5]  Bruce G. Jenkins,et al.  Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Peter van Gelderen,et al.  Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells , 2001, Nature Biotechnology.

[7]  Benjamin E. Reubinoff,et al.  Neural progenitors from human embryonic stem cells , 2001, Nature Biotechnology.

[8]  Marius Wernig,et al.  In vitro differentiation of transplantable neural precursors from human embryonic stem cells , 2001, Nature Biotechnology.

[9]  R Weissleder,et al.  Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles. , 2001, Journal of immunological methods.

[10]  Jeff W. M. Bulte,et al.  Synthesis and Characterization of Soluble Iron Oxide−Dendrimer Composites , 2001 .

[11]  J. Kocsis,et al.  Transplantation of Cryopreserved Adult Human Schwann Cells Enhances Axonal Conduction in Demyelinated Spinal Cord , 2001, The Journal of Neuroscience.

[12]  J. Kocsis,et al.  Transplantation of Clonal Neural Precursor Cells Derived from Adult Human Brain Establishes Functional Peripheral Myelin in the Rat Spinal Cord , 2001, Experimental Neurology.

[13]  Bradley D. Smith,et al.  High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model. , 2000, Bioconjugate chemistry.

[14]  J. Kocsis,et al.  Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord , 2000, Nature Biotechnology.

[15]  A. Crang,et al.  Transplanted glial cells migrate over a greater distance and remyelinate demyelinated lesions more rapidly than endogenous remyelinating cells , 2000, Journal of neuroscience research.

[16]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[17]  J A Frank,et al.  Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Franklin,et al.  Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain. , 1999, Neuroreport.

[19]  J. García-Verdugo,et al.  Adult‐derived neural precursors transplanted into multiple regions in the adult brain , 1999, Annals of neurology.

[20]  M. Rovaris,et al.  Method for intracellular magnetic labeling of human mononuclear cells using approved iron contrast agents. , 1999, Magnetic resonance imaging.

[21]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[22]  I. Duncan,et al.  Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin , 1999, Annals of neurology.

[23]  R. Brooks,et al.  Relaxometry and magnetometry of the MR contrast agent MION‐46L , 1999, Magnetic resonance in medicine.

[24]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[25]  E. Snyder,et al.  "Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  I. Duncan,et al.  Insertion of a Retrotransposon in Mbp Disrupts mRNA Splicing and Myelination in a New Mutant Rat , 1999, The Journal of Neuroscience.

[27]  I. Duncan,et al.  Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R Weissleder,et al.  High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. , 1999, Bioconjugate chemistry.

[29]  Jonas Frisén,et al.  Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System , 1999, Cell.

[30]  Donald S. Williams,et al.  Detection of single mammalian cells by high-resolution magnetic resonance imaging. , 1999, Biophysical journal.

[31]  Peter J. Donovan,et al.  Derivation of pluripotent stem cells from cultured human primordial germ cells , 1998 .

[32]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[33]  R. Sidman,et al.  Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes , 1998, Nature Biotechnology.

[34]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[35]  R. Jain,et al.  Intracellular magnetic labeling of lymphocytes for in vivo trafficking studies. , 1998, BioTechniques.

[36]  R. Juliano,et al.  Characterization of complexes of oligonucleotides with polyamidoamine starburst dendrimers and effects on intracellular delivery. , 1997, Journal of pharmaceutical sciences.

[37]  J. Bulte,et al.  Magnetic Nanoparticles as Contrast Agents for MR Imaging , 1997 .

[38]  R Weissleder,et al.  Magnetically labeled cells can be detected by MR imaging , 1997, Journal of magnetic resonance imaging : JMRI.

[39]  I. Duncan,et al.  Myelination of the canine central nervous system by glial cell transplantation: A model for repair of human myelin disease , 1997, Nature Medicine.

[40]  F. Szoka,et al.  In vitro gene delivery by degraded polyamidoamine dendrimers. , 1996, Bioconjugate chemistry.

[41]  K. Mechtler,et al.  Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. , 1996, Human gene therapy.

[42]  J. Bulte,et al.  Tagging of T cells with superparamagnetic iron oxide: uptake kinetics and relaxometry. , 1996, Academic radiology.

[43]  J. Baker,et al.  Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[44]  I. Duncan Glial cell transplanatation and remyelination of the central nervous system , 1996 .

[45]  I. Duncan Glial cell transplantation and remyelination of the central nervous system. , 1996, Neuropathology and Applied Neurobiology.

[46]  R. Franklin,et al.  Glial cell transplants that are subsequently rejected can be used to influence regeneration of glial cell environments in the CNS , 1995, Glia.

[47]  Chien Ho,et al.  In Vivo Dynamic MRI Tracking of Rat T‐Cells Labeled with Superparamagnetic Iron‐Oxide Particles , 1995, Magnetic resonance in medicine.

[48]  R. Franklin,et al.  Differentiation of the O‐2A progenitor cell line CG‐4 into oligodendrocytes and astrocytes following transplantation into glia‐deficient areas of CNS white matter , 1995, Glia.

[49]  I. Duncan,et al.  Transplantation of an oligodendrocyte cell line leading to extensive myelination. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  S. Waxman,et al.  Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin-deficient rat. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[51]  I. Duncan,et al.  Transplantation of Myelinating Cells into the Central Nervous System , 1994 .

[52]  Chien Ho,et al.  Intracellular labeling of T‐cells with superparamagnetic contrast agents , 1993, Magnetic resonance in medicine.

[53]  Pratik Ghosh,et al.  Nuclear Magnetic Resonance (NMR) Imaging of Iron Oxide-Labeled Neural Transplants , 1993, Experimental Neurology.

[54]  R Weissleder,et al.  Monocrystalline iron oxide nanocompounds (MION): Physicochemical properties , 1993, Magnetic resonance in medicine.

[55]  R. Franklin,et al.  Repair of demyelinated lesions by transplantation of purified 0-2A progenitor cells , 1993, Nature.

[56]  E. Cho,et al.  Multiple sclerosis: Remyelination of nascent lesions: Remyelination of nascent lesions , 1993 .

[57]  J. Bulte,et al.  Selective MR imaging of labeled human peripheral blood mononuclear cells by liposome mediated incorporation of dextran‐magnetite particles , 1993, Magnetic resonance in medicine.

[58]  J. de Vellis,et al.  O2A progenitor cells transplanted into the neonatal rat brain develop into oligodendrocytes but not astrocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[59]  E. Cho,et al.  Multiple sclerosis: remyelination of nascent lesions. , 1993, Annals of neurology.

[60]  Photoconverted carbocyanine DiI allows direct visualization of transplanted glial cells at the ultrastructural level , 1992, Neuroscience Letters.

[61]  Stephen R. Thomas,et al.  Magnetic resonance imaging of neural transplants in rat brain using a superparamagnetic contrast agent , 1992, Brain Research.

[62]  A. Harvey,et al.  Survival and migration of transplanted male glia in adult female mouse brains monitored by a Y-chromosome-specific probe. , 1992, Brain research. Molecular brain research.

[63]  D. Muir,et al.  CG‐4, A new bipotential glial cell line from rat brain, is capable of differentiating in vitro into either mature oligodendrocytes or type‐2 astrocytes , 1992, Journal of neuroscience research.

[64]  J. de Vellis,et al.  Transplantation of cultured premyelinating oligodendrocytes into normal and myelin-deficient rat brain. , 1992, Developmental neuroscience.

[65]  A. B. Evercooren,et al.  Hoechst 33342 a suitable fluorescent marker for Schwann cells after transplantation in the mouse spinal cord , 1991, Neuroscience Letters.

[66]  R. Franklin,et al.  Transplantation of glial cells into the CNS , 1991, Trends in Neurosciences.

[67]  R Weissleder,et al.  Superparamagnetic iron oxide: pharmacokinetics and toxicity. , 1989, AJR. American journal of roentgenology.

[68]  I. Duncan,et al.  Transplantation of oligodendrocytes and Schwann cells into the spinal cord of the myelin-deficient rat , 1988, Journal of neurocytology.

[69]  W. Jefferies,et al.  Transferrin receptor on endothelium of brain capillaries , 1984, Nature.

[70]  G. Raisman,et al.  An autoradiographic study of neuronal development, vascularization and glial cell migration from hippocampal transplants labelled in intermediate explant culture , 1984, Neuroscience.

[71]  M. Baulac,et al.  Transplantation of CNS fragments into the brain of shiverer mutant mice: extensive myelination by implanted oligodendrocytes. I. Immunohistochemical studies. , 1983, Developmental neuroscience.

[72]  L. Scheinberg,et al.  Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. , 1981, Laboratory investigation; a journal of technical methods and pathology.