The transplantation of mesenchymal stem cells (MSC) is currently under study as a therapeutic approach for spinal cord injury, and the number of transplanted cells that reach the lesioned tissue is one of the critical parameters. In this study, intrathecally transplanted cells labeled with superparamagnetic iron oxide nanoparticles were guided by a magnetic field and successfully targeted near the lesion site in the rat spinal cord. Magnetic resonance imaging and histological analysis revealed significant differences in cell numbers and cell distribution near the lesion site under the magnet in comparison to control groups. The cell distribution correlated well with the calculated distribution of magnetic forces exerted on the transplanted cells in the subarachnoid space and lesion site. The kinetics of the cells' accumulation near the lesion site is described within the framework of a mathematical model that reveals those parameters critical for cell targeting and suggests ways to enhance the efficiency of magnetic cell delivery. In particular, we show that the targeting efficiency can be increased by using magnets that produce spatially modulated stray fields. Such magnetic systems with tunable geometric parameters may provide the additional level of control needed to enhance the efficiency of stem cell delivery in spinal cord injury.

Institute of Experimental Medicine AS CR Prague Czech Republic

Zobrazit více v PubMed

Kubinova S, Sykova E. Biomaterials combined with cell therapy for treatment of spinal cord injury. Regen Med. 2012;7(2):207–224. PubMed

Talac R, Friedman JA, Moore MJ, et al. Animal models of spinal cord injury for evaluation of tissue engineering treatment strategies. Biomaterials. 2004;25(9):1505–1510. PubMed

Sykova E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006;15(8–9):675–687. PubMed

Arboleda D, Forostyak S, Jendelova P, et al. Transplantation of predifferentiated adipose-derived stromal cells for the treatment of spinal cord injury. Cell Mol Neurobiol. 2011;31(7):1113–1122. PubMed

Kim J, Kim IS, Cho TH, et al. Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells. Biomaterials. 2007;28(10):1830–1837. PubMed

Fan H, Hu Y, Zhang C, et al. Cartilage regeneration using mesenchymal stem cells and a PLGA-gelatin/chondroitin/hyaluronate hybrid scaffold. Biomaterials. 2006;27(26):4573–4580. PubMed

Gaebel R, Ma N, Liu J, et al. Patterning human stem cells and endothelial cells with laser printing for cardiac regeneration. Biomaterials. 2011;32(35):9218–9230. PubMed

Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95(2):213–228. PubMed PMC

Forostyak S, Jendelova P, Kapcalova M, Arboleda D, Sykova E. Mesenchymal stromal cells prolong the lifespan in a rat model of amyotrophic lateral sclerosis. Cytotherapy. 2011;13(9):1036–1046. PubMed

Kubinova S, Sykova E. Nanotechnology for treatment of stroke and spinal cord injury. Nanomedicine (Lond) 2010;5(1):99–108. PubMed

Urdzikova L, Jendelova P, Glogarova K, Burian M, Hajek M, Sykova E. Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats. J Neurotrauma. 2006;23(9):1379–1391. PubMed

Osaka M, Honmou O, Murakami T, et al. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res. 2010;1343:226–235. PubMed

Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1(2):92–100. PubMed

Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia. 2002;39(3):229–236. PubMed PMC

Chen X, Katakowski M, Li Y, et al. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res. 2002;69(5):687–691. PubMed

Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;1105(4):5. 1815–1822. PubMed

Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol. 2006;198(1):54–64. PubMed

Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009;3:63–70. PubMed

Paul C, Samdani AF, Betz RR, Fischer I, Neuhuber B. Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976) 2009:328–334. PubMed PMC

Jendelova P, Herynek V, Urdzikova L, et al. Magnetic resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J Neurosci Res. 2004;76(2):232–243. PubMed

Sykova 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;1049:146–160. PubMed

Huang Z, Pei N, Wang Y, et al. Deep magnetic capture of magnetically loaded cells for spatially targeted therapeutics. Biomaterials. 2010;31(8):2130–2140. PubMed

Wilhelm C, Bal L, Smirnov P, et al. Magnetic control of vascular network formation with magnetically labeled endothelial progenitor cells. Biomaterials. 2007;28(26):3797–3806. PubMed

Arbab AS, Jordan EK, Wilson LB, Yocum GT, Lewis BK, Frank JA. In vivo trafficking and targeted delivery of magnetically labeled stem cells. Hum Gene Ther. 2004;15(4):351–360. PubMed

Song M, Kim YJ, Kim YH, Roh J, Kim SU, Yoon BW. Using a neodymium magnet to target delivery of ferumoxide-labeled human neural stem cells in a rat model of focal cerebral ischemia. Hum Gene Ther. 2010;21(5):603–610. PubMed

Nishida K, Tanaka N, Nakanishi K, et al. Magnetic targeting of bone marrow stromal cells into spinal cord: through cerebrospinal fluid. Neuroreport. 2006;217(12):1. 1269–1272. PubMed

Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–317. PubMed

Babic M, Horak D, Trchova M, et al. Poly(L-lysine)-modified iron oxide nanoparticles for stem cell labeling. Bioconjug Chem. 2008;19(3):740–750. PubMed

De la Calle JL, Paino CL. A procedure for direct lumbar puncture in rats. Brain Res Bull. 2002;59(3):245–250. PubMed

Mothe AJ, Tator CH. Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol. 2008;213(1):176–190. PubMed

Zablotskii V, Pastor JM, Larumbe S, et al. High-field gradient permanent micromagnets for targeted drug delivery with magnetic nanoparticles. AIP Conf Proc. 2010;1311:152–157.

Pankhurst QA, Connolly J, Jones SK, Dobson J. Applications of magnetic nanoparticles in biomedicine. J Phys D Appl Phys. 2003;36(13):R167–181.

Zablotskii V, Lunov O, Dejneka A, et al. Nanomechanics of magnetically driven cellular endocytosis. Appl Phys Lett. 2011;99(18):183701–183703.

Mothe AJ, Bozkurt G, Catapano J, et al. Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat. Spinal Cord. 2011;49(9):967–973. PubMed

Horak D, Babic M, Jendelova P, et al. Effect of different magnetic nanoparticle coatings on the efficiency of stem cell labeling. J Magn Magn Mater. 2009;321(10):1539–1547.

Cheng K, Li TS, Malliaras K, Davis DR, Zhang Y, Marban E. Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction. Circ Res. 2010;106(10):1570–1581. PubMed PMC

Schafer R, Bantleon R, Kehlbach R, et al. Functional investigations on human mesenchymal stem cells exposed to magnetic fields and labeled with clinically approved iron nanoparticles. BMC Cell Biol. 2010;11:22. PubMed PMC

Sykova E, Jendelova P, Urdzikova L, Lesny P, Hejcl A. Bone marrow stem cells and polymer hydrogels–two strategies for spinal cord injury repair. Cell Mol Neurobiol. 2006;26(7–8):1113–1129. PubMed

Bakshi A, Hunter C, Swanger S, Lepore A, Fischer I. Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J Neurosurg Spine. 2004;1(3):330–337. PubMed

Satake K, Lou J, Lenke LG. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue. Spine (Phila Pa 1976) 2004;29(18):1971–1979. PubMed

Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8:7. PubMed PMC

Di Chiro G. Observations on the circulation of the cerebrospinal fluid. Acta Radiol Diagn (Stockh) 1966;5:988–1002. PubMed

Greitz D, Hannerz J. A proposed model of cerebrospinal fluid circulation: observations with radionuclide cisternography. AJNR Am J Neuroradiol. 1996;17(3):431–438. PubMed PMC

Linninger AA, Xenos M, Sweetman B, Ponkshe S, Guo X, Penn R. A mathematical model of blood, cerebrospinal fluid and brain dynamics. J Math Biol. 2009;59(6):729–759. PubMed

Sasaki H, Tanaka N, Nakanishi K, et al. Therapeutic effects with magnetic targeting of bone marrow stromal cells in a rat spinal cord injury model. Spine (Phila Pa 1976) 2011;36(12):933–938. PubMed

Häfeli UO, Gilmour K, Zhou A, Lee S, Hayden ME. Modeling of magnetic bandages for drug targeting: Button vs Halbach arrays. J Magn Magn Mater. 2007;311(1):323–329.

Novotna B, Jendelova P, Kapcalova M, et al. Oxidative damage to biological macromolecules in human bone marrow mesenchymal stromal cells labeled with various types of iron oxide nanoparticles. Toxicol Lett. 2012;210(1):53–63. PubMed

Biomaterials and Magnetic Stem Cell Delivery in the Treatment of Spinal Cord Injury

The effects of grafted mesenchymal stem cells labeled with iron oxide or cobalt-zinc-iron nanoparticles on the biological macromolecules of rat brain tissue extracts

Stem Cells and Labeling for Spinal Cord Injury

Human mesenchymal stem cells modulate inflammatory cytokines after spinal cord injury in rat