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http://dx.doi.org/10.3340/jkns.2013.54.6.467

Engraftment of Human Mesenchymal Stem Cells in a Rat Photothrombotic Cerebral Infarction Model : Comparison of Intra-Arterial and Intravenous Infusion Using MRI and Histological Analysis  

Byun, Jun Soo (Department of Radiology, Chung-Ang University College of Medicine)
Kwak, Byung Kook (Department of Radiology, Chung-Ang University College of Medicine)
Kim, Jae Kyun (Department of Radiology, Chung-Ang University College of Medicine)
Jung, Jisung (Department of Radiology, Chung-Ang University College of Medicine)
Ha, Bon Chul (Department of Radiology, Chung-Ang University College of Medicine)
Park, Serah (Department of Radiology, Chung-Ang University College of Medicine)
Publication Information
Journal of Korean Neurosurgical Society / v.54, no.6, 2013 , pp. 467-476 More about this Journal
Abstract
Objective : This study aimed to evaluate the hypotheses that administration routes [intra-arterial (IA) vs. intravenous (IV)] affect the early stage migration of transplanted human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in acute brain infarction. Methods : Male Sprague-Dawley rats (n=40) were subjected to photothrombotic infarction. Three days after photothrombotic infarction, rats were randomly allocated to one of four experimental groups [IA group : n=12, IV group : n=12, superparamagnetic iron oxide (SPIO) group : n=8, control group : n=8]. All groups were subdivided into 1, 6, 24, and 48 hours groups according to time point of sacrifice. Magnetic resonance imaging (MRI) consisting of T2 weighted image (T2WI), $T2^*$ weighted image ($T2^*WI$), susceptibility weighted image (SWI), and diffusion weighted image of rat brain were obtained prior to and at 1, 6, 24, and 48 hours post-implantation. After final MRI, rats were sacrificed and grafted cells were analyzed in brain and lung specimen using Prussian blue and immunohistochemical staining. Results : Grafted cells appeared as dark signal intensity regions at the peri-lesional zone. In IA group, dark signals in peri-lesional zone were more prominent compared with IV group. SWI showed largest dark signal followed by $T2^*WI$ and T2WI in both IA and IV groups. On Prussian blue staining, IA administration showed substantially increased migration and a large number of transplanted hBM-MSCs in the target brain than IV administration. The Prussian blue-positive cells were not detected in SPIO and control groups. Conclusion : In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration. MRI and histological analyses revealed the time course of cell migration, and the numbers and distribution of hBM-MSCs delivered into the brain.
Keywords
MRI; Mesenchymal stem cell; Photothrombotic cerebral infarction; Superparamagnetic iron oxide; Intravascular;
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1 Shichinohe H, Kuroda S, Yano S, Ohnishi T, Tamagami H, Hida K, et al. : Improved expression of gamma-aminobutyric acid receptor in mice with cerebral infarct and transplanted bone marrow stromal cells : an autoradiographic and histologic analysis. J Nucl Med 47 : 486-491, 2006
2 Tran PB, Ren D, Veldhouse TJ, Miller RJ : Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. J Neurosci Res 76 : 20-34, 2004   DOI   ScienceOn
3 Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, et al. : Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 39 : 1569-1574, 2008   DOI   ScienceOn
4 Wang Q, Tang XN, Yenari MA : The inflammatory response in stroke. J Neuroimmunol 184 : 53-68, 2007   DOI   ScienceOn
5 Wang Y, Deng Y, Zhou GQ : SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195 : 104-112, 2008   DOI   ScienceOn
6 Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD : Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol 17 : 497-504, 1985   DOI   ScienceOn
7 Wislet-Gendebien S, Hans G, Leprince P, Rigo JM, Moonen G, Rogister B : Plasticity of cultured mesenchymal stem cells : switch from nestin-positive to excitable neuron-like phenotype. Stem Cells 23 : 392-402, 2005   DOI   ScienceOn
8 Witte OW, Stoll G : Delayed and remote effects of focal cortical infarctions : secondary damage and reactive plasticity. Adv Neurol 73 : 207-227, 1997
9 Yang M, Wei X, Li J, Heine LA, Rosenwasser R, Iacovitti L : Changes in host blood factors and brain glia accompanying the functional recovery after systemic administration of bone marrow stem cells in ischemic stroke rats. Cell Transplant 19 : 1073-1084, 2010   DOI   ScienceOn
10 Zhu J, Zhou Z, Liu Y, Zheng J : Fractalkine and CX3CR1 are involved in the migration of intravenously grafted human bone marrow stromal cells toward ischemic brain lesion in rats. Brain Res 1287 : 173-183, 2009   DOI   ScienceOn
11 McAuley MA : Rodent models of focal ischemia. Cerebrovasc Brain Metab Rev 7 : 153-180, 1995
12 Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR : Turning blood into brain : cells bearing neuronal antigens generated in vivo from bone marrow. Sience 290 : 1779-1782, 2000   DOI   ScienceOn
13 Parr AM, Tator CH, Keating A : Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 40 : 609-619, 2007   DOI   ScienceOn
14 Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, Wang H, et al. : Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 41 : 2064-2070, 2010   DOI   ScienceOn
15 Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, et al. : Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436 : 266-271, 2005   DOI   ScienceOn
16 Rebenko-Moll NM, Liu L, Cardona A, Ransohoff RM : Chemokines, mononuclear cells and the nervous system : heaven (or hell) is in the details. Curr Opin Immunol 18 : 683-689, 2006   DOI   ScienceOn
17 Reddy AM, Kwak BK, Shim HJ, Ahn C, Cho SH, Kim BJ, et al. : Functional characterization of mesenchymal stem cells labeled with a novel PVP-coated superparamagnetic iron oxide. Contrast Media Mol Imaging 4 : 118-126, 2009   DOI   ScienceOn
18 Sehgal V, Delproposto Z, Haddar D, Haacke EM, Sloan AE, Zamorano LJ, et al. : Susceptibility-weighted imaging to visualize blood products and improve tumor contrast in the study of brain masses. J Magn Reson Imaging 24 : 41-51, 2006   DOI   ScienceOn
19 Reichenbach JR, Venkatesan R, Schillinger DJ, Kido DK, Haacke EM : Small vessels in the human brain : MR venography with deoxyhemoglobin as an intrinsic contrast agent. Radiology 204 : 272-277, 1997   DOI
20 Sehgal V, Delproposto Z, Haacke EM, Tong KA, Wycliffe N, Kido DK, et al. : Clinical applications of neuroimaging with susceptibility-weighted imaging. J Magn Reson Imaging 22 : 439-450, 2005   DOI   ScienceOn
21 Shen LH, Li Y, Chen J, Zhang J, Vanguri P, Borneman J, et al. : Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience 137 : 393-399, 2006   DOI   ScienceOn
22 Kitagawa K, Matsumoto M, Yang G, Mabuchi T, Yagita Y, Hori M, et al. : Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice : evaluation of the patency of the posterior communicating artery. J Cereb Blood Flow Metab 18 : 570-579, 1998   DOI
23 Lee JK, Park MS, Kim YS, Moon KS, Joo SP, Kim TS, et al. : Photochemically induced cerebral ischemia in a mouse model. Surg Neurol 67 : 620-625; discussion 625, 2007   DOI   ScienceOn
24 Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY; STARTING collaborators : A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28 : 1099-1106, 2010   DOI   ScienceOn
25 Leor J, Rozen L, Zuloff-Shani A, Feinberg MS, Amsalem Y, Barbash IM, et al. : Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation 114 (1 Suppl) :I94-I100, 2006
26 Li L, Jiang Q, Ding G, Zhang L, Zhang ZG, Li Q, et al. : Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. J Cereb Blood Flow Metab 30 : 653-662, 2010   DOI   ScienceOn
27 Lundberg J, Le Blanc K, Söderman M, Andersson T, Holmin S : Endovascular transplantation of stem cells to the injured rat CNS. Neuroradiology 51 : 661-667, 2009   DOI
28 Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, et al. : Human marrow stromal cell therapy for stroke in rat : neurotrophins and functional recovery. Neurology 59 : 514-523, 2002   DOI   ScienceOn
29 Li Y, Chen J, Zhang CL, Wang L, Lu D, Katakowski M, et al. : Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia 49 : 407-417, 2005   DOI   ScienceOn
30 Liu W, Jiang X, Fu X, Cui S, Du M, Cai Y, et al. : Bone marrow stromal cells can be delivered to the site of traumatic brain injury via intrathecal transplantation in rabbits. Neurosci Lett 434 : 160-164, 2008   DOI   ScienceOn
31 Luria EA, Panasyuk AF, Friedenstein AY : Fibroblast colony formation from monolayer cultures of blood cells. Transfusion 11 : 345-349, 1971   DOI   ScienceOn
32 Magnitsky S, Watson DJ, Walton RM, Pickup S, Bulte JW, Wolfe JH, et al. : In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain. Neuroimage 26 : 744-754, 2005   DOI   ScienceOn
33 Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. : Pulmonary passage is a major obstacle for intravenous stem cell delivery : the pulmonary first-pass effect. Stem Cells Dev 18 : 683-692, 2009   DOI   ScienceOn
34 Friedenstein AJ, Chailakhjan RK, Lalykina KS : The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3 : 393-403, 1970
35 Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, et al. : Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 41 : 1841-1846, 2003   DOI   ScienceOn
36 Guzman R, Choi R, Gera A, De Los Angeles A, Andres RH, Steinberg GK : Intravascular cell replacement therapy for stroke. Neurosurg Focus 24 : E15, 2008
37 Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA, et al. : Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108 : 1009-1014, 2003   DOI   ScienceOn
38 Guzman R, De Los Angeles A, Cheshier S, Choi R, Hoang S, Liauw J, et al. : Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke 39 : 1300-1306, 2008   DOI   ScienceOn
39 Haacke EM, Xu Y, Cheng YC, Reichenbach JR : Susceptibility weighted imaging (SWI). Magn Reson Med 52 : 612-618, 2004   DOI   ScienceOn
40 Hicks A, Jolkkonen J : Challenges and possibilities of intravascular cell therapy in stroke. Acta Neurobiol Exp (Wars) 69 : 1-11, 2009
41 Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, et al. : Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134 (Pt 6) : 1790-1807, 2011   DOI   ScienceOn
42 Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, et al. : Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis 18 : 366-374, 2005   DOI   ScienceOn
43 Kassem M : Mesenchymal stem cells : biological characteristics and potential clinical applications. Cloning Stem Cells 6 : 369-374, 2004   DOI   ScienceOn
44 Buchkremer-Ratzmann I, August M, Hagemann G, Witte OW : Electrophysiological transcortical diaschisis after cortical photothrombosis in rat brain. Stroke 27 : 1105-1109; discussion 1109-1111, 1996   DOI   ScienceOn
45 Bulte JW, Kraitchman DL : Monitoring cell therapy using iron oxide MR contrast agents. Curr Pharm Biotechnol 5 : 567-584, 2004   DOI   ScienceOn
46 Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, et al. : Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73 : 778-786, 2003   DOI   ScienceOn
47 Chopp M, Li Y : Treatment of neural injury with marrow stromal cells. Lancet Neurol 1 : 92-100, 2002   DOI   ScienceOn
48 Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M : Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189 : 49-57, 2001   DOI   ScienceOn
49 Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, et al. : Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92 : 692-699, 2003   DOI   ScienceOn
50 Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J, et al. : Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology 22 : 275-279, 2002   DOI   ScienceOn
51 Chu K, Kim M, Park KI, Jeong SW, Park HK, Jung KH, et al. : Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res 1016 : 145-153, 2004   DOI   ScienceOn
52 Clark WM, Lessov NS, Dixon MP, Eckenstein F : Monofilament intraluminal middle cerebral artery occlusion in the mouse. Neurol Res 19 : 641-648, 1997   DOI
53 Cui X, Chen J, Zacharek A, Li Y, Roberts C, Kapke A, et al. : Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. Stem Cells 25 : 2777-2785, 2007   DOI   ScienceOn
54 Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, et al. : Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113 : 1701-1710, 2004   DOI
55 Andres RH, Choi R, Steinberg GK, Guzman R : Potential of adult neural stem cells in stroke therapy. Regen Med 3 : 893-905, 2008   DOI   ScienceOn
56 Abdallah BM, Haack-Sorensen M, Burns JS, Elsnab B, Jakob F, Hokland P, et al. : Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation. Biochem Biophys Res Commun 326 : 527-538, 2005   DOI   ScienceOn
57 Akter M, Hirai T, Hiai Y, Kitajima M, Komi M, Murakami R, et al. : Detection of hemorrhagic hypointense foci in the brain on susceptibility-weighted imaging clinical and phantom studies. Acad Radiol 14 : 1011-1019, 2007   DOI   ScienceOn
58 Andres RH, Choi R, Pendharkar AV, Gaeta X, Wang N, Nathan JK, et al. : The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain. Stroke 42 : 2923-2931, 2011   DOI   ScienceOn
59 Arai T, Kofidis T, Bulte JW, de Bruin J, Venook RD, Berry GJ, et al. : Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t. Magn Reson Med 55 : 203-209, 2006   DOI   ScienceOn
60 Bang OY, Lee JS, Lee PH, Lee G : Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57 : 874-882, 2005   DOI   ScienceOn
61 Barry FP, Murphy JM : Mesenchymal stem cells : clinical applications and biological characterization. Int J Biochem Cell Biol 36 : 568-584, 2004   DOI   ScienceOn
62 Borlongan CV, Lind JG, Dillon-Carter O, Yu G, Hadman M, Cheng C, et al. : Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats. Brain Res 1010 : 108-116, 2004   DOI   ScienceOn
63 Borlongan CV, Lind JG, Dillon-Carter O, Yu G, Hadman M, Cheng C, et al. : Intracerebral xenografts of mouse bone marrow cells in adult rats facilitate restoration of cerebral blood flow and blood-brain barrier. Brain Res 1009 : 26-33, 2004   DOI   ScienceOn
64 Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, et al. : Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27 : 6-13, 2007   DOI   ScienceOn
65 Brazelton TR, Rossi FM, Keshet GI, Blau HM : From marrow to brain : expression of neuronal phenotypes in adult mice. Science 290 : 1775-1779, 2000   DOI   ScienceOn
66 Frijns CJ, Kappelle LJ : Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 33 : 2115-2122, 2002   DOI   ScienceOn
67 Woodbury D, Schwarz EJ, Prockop DJ, Black IB : Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61 : 364-370, 2000   DOI   ScienceOn