Transplanted bone marrow stromal cells improves cognitive dysfunction due to diffuse axonal injury in rats
Katsuhiko Maruichi,
Satoshi Kuroda,
Yasuhiro Chiba,
Masaaki Hokari,
Hideo Shichinohe,
Kazutoshi Hida,
Yoshinobu Iwasaki,
Katsuhiko Maruichi
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorSatoshi Kuroda
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorYasuhiro Chiba
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorMasaaki Hokari
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorHideo Shichinohe
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorKazutoshi Hida
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorYoshinobu Iwasaki
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorKatsuhiko Maruichi,
Satoshi Kuroda,
Yasuhiro Chiba,
Masaaki Hokari,
Hideo Shichinohe,
Kazutoshi Hida,
Yoshinobu Iwasaki,
Katsuhiko Maruichi
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorSatoshi Kuroda
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorYasuhiro Chiba
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorMasaaki Hokari
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorHideo Shichinohe
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorKazutoshi Hida
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorYoshinobu Iwasaki
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Search for more papers by this authorSatoshi Kuroda, MD, PhD, Department of Neurosurgery, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Email: [email protected]
Abstract
Diffuse axonal injury (DAI) often leads to persistent cognitive dysfunction in spite of the lack of gross lesions on MRI. Therefore, this study was aimed to evaluate whether transplanted bone marrow stromal cells (BMSC) can improve DAI-induced cognitive dysfunction or not. The rats were subjected to impact acceleration head injury, using a pneumatic high-velocity impactor. The BMSC were harvested from the mice and were cultured. The BMSC (4.0 × 105 cells) or vehicle were stereotactically transplanted into the right striatum at 10 days post-injury. Cognitive function analysis was repeated at 1, 2, and 4 weeks post-injury, using the Morris water maze test. Histological analysis was performed at 2, 8 and 20 weeks post-injury, using double fluorescence immunohistochemistry. Transplanted BMSC were widely distributed in the injured brain and gradually acquired the phenotypes of neurons and astrocytes over 20 weeks. In addition, they significantly improved DAI-induced cognitive dysfunction as early as 2 weeks post-injury, although their processes of neuronal differentiation were not completed at this time point. The findings suggest that the engrafted BMSC may exhibit this early beneficial effect on cognitive function by producing neuroprotective or neurotrophic factors. In conclusion, direct transplantation of BMSC may serve as a novel therapeutic strategy to enhance the recovery from DAI-induced cognitive impairment.
REFERENCES
- 1 Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol 1982; 12: 557–563.
- 2 Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982; 12: 564–574.
- 3 Povlishock JT. Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol 1992; 2: 1–12.
- 4 Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats–similarities to astrocyte grafts. Proc Natl Acad Sci USA 1998; 95: 3908–3913.
- 5 Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999; 96: 10711–10716.
- 6 Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61: 364–370.
- 7 Hokari M, Kuroda S, Shichinohe H, Yano S, Hida K, Iwasaki Y. Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms. J Neurosci Res 2008; 86: 1024–1035.
- 8 Lu D, Li Y, Mahmood A, Wang L, Rafiq T, Chopp M. Neural and marrow-derived stromal cell sphere transplantation in a rat model of traumatic brain injury. J Neurosurg 2002; 97: 935–940.
- 9 Lu D, Li Y, Wang L, Chen J, Mahmood A, Chopp M. Intraarterial administration of marrow stromal cells in a rat model of traumatic brain injury. J Neurotrauma 2001; 18: 813–819.
- 10 Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 2001; 12: 559–563.
- 11 Lu J, Moochhala S, Moore XL et al. Adult bone marrow cells differentiate into neural phenotypes and improve functional recovery in rats following traumatic brain injury. Neurosci Lett 2006; 398: 12–17.
- 12 Mahmood A, Lu D, Chopp M. Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery 2004; 55: 1185–1193.
- 13 Mahmood A, Lu D, Lu M, Chopp M. Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery 2003; 53: 697–702; discussion 2–3.
- 14 Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery 2005; 57: 1026–1031; discussion 26–31.
- 15 Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats. J Neurosurg 2006; 104: 272–277.
- 16 Mahmood A, Lu D, Wang L, Chopp M. Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. J Neurotrauma 2002; 19: 1609–1617.
- 17 Mahmood A, Lu D, Wang L, Li Y, Lu M, Chopp M. Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 2001; 49: 1196–1203; discussion 203–204.
- 18 Lu D, Mahmood A, Qu C, Hong X, Kaplan D, Chopp M. Collagen scaffolds populated with human marrow stromal cells reduce lesion volume and improve functional outcome after traumatic brain injury. Neurosurgery 2007; 61: 596–602; discussion 2–3.
- 19 Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats. Neurosurgery 2007; 60: 546–553; discussion 53–54.
- 20 Cernak I. Animal models of head trauma. NeuroRx 2005; 2: 410–422.
- 21 Shichinohe H, Kuroda S, Lee JB et al. In vivo tracking of bone marrow stromal cells transplanted into mice cerebral infarct by fluorescence optical imaging. Brain Res Brain Res Protoc 2004; 13: 166–175.
- 22 Shichinohe H, Kuroda S, Yano S 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 2006; 47: 486–491.
- 23 Shichinohe H, Kuroda S, Tsuji S et al. Bone marrow stromal cells differentiate into neurons and promote axon elongation in spinal cord slice cultures: their role in cell transplantation therapy for spinal cord injury. Neurorehabil Neural Repair 2008; 22: 447–457.
- 24 Yano S, Kuroda S, Lee JB et al. In vivo fluorescence tracking of bone marrow stromal cells transplanted into a pneumatic injury model of rat spinal cord. J Neurotrauma 2005; 22: 907–918.
- 25 Yano S, Kuroda S, Shichinohe H, Hida K, Iwasaki Y. Do bone marrow stromal cells proliferate after transplantation into mice cerebral infarct?–a double labeling study. Brain Res 2005; 1065: 60–67.
- 26 Yano S, Kuroda S, Shichinohe H et al. Bone marrow stromal cell transplantation preserves gammaaminobutyric acid receptor function in the injured spinal cord. J Neurotrauma 2006; 23: 1682–1692.
- 27 Cernak I, Vink R, Zapple DN et al. The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats. Neurobiol Dis 2004; 17: 29–43.
- 28 Maruichi K, Kuroda S, Chiba Y et al. Graded model of diffuse axonal injury for studying head injury-induced cognitive dysfunction in rats. Neuropathology 2009 (in press).
- 29 Seki T, Hida K, Tada M, Koyanagi I, Iwasaki Y. Graded contusion model of the mouse spinal cord using a pneumatic impact device. Neurosurgery 2002; 50: 1075–1081; discussion 81–82.
- 30 Seki T, Hida K, Tada M, Koyanagi I, Iwasaki Y. Role of the bcl-2 gene after contusive spinal cord injury in mice. Neurosurgery 2003; 53: 192–198; discussion 98.
- 31 Lee JB, Kuroda S, Shichinohe H et al. Migration and differentiation of nuclear fluorescence-labeled bone marrow stromal cells after transplantation into cerebral infarct and spinal cord injury in mice. Neuropathology 2003; 23: 169–180.
- 32 Lee JB, Kuroda S, Shichinohe H et al. A pre-clinical assessment model of rat autogeneic bone marrow stromal cell transplantation into the central nervous system. Brain Res Brain Res Protoc 2004; 14: 37–44.
- 33 Shichinohe H, Kuroda S, Yano S, Hida K, Iwasaki Y. Role of SDF-1/CXCR4 system in survival and migration of bone marrow stromal cells after transplantation into mice cerebral infarct. Brain Res 2007; 1138: 138–147.
- 34 Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11: 47–60.
- 35 Sinson G, Voddi M, McIntosh TK. Combined fetal neural transplantation and nerve growth factor infusion: effects on neurological outcome following fluid-percussion brain injury in the rat. J Neurosurg 1996; 84: 655–662.
- 36 Philips MF, Mattiasson G, Wieloch T et al. Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury. J Neurosurg 2001; 94: 765–774.
- 37 Watson DJ, Longhi L, Lee EB et al. Genetically modified NT2N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury. J Neuropathol Exp Neurol 2003; 62: 368–380.
- 38 Bakshi A, Shimizu S, Keck CA et al. Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury. Eur J Neurosci 2006; 23: 2119–2134.
- 39 Gao J, Prough DS, McAdoo DJ et al. Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury. Exp Neurol 2006; 201: 281–292.
- 40 Chen Y, Constantini S, Trembovler V, Weinstock M, Shohami E. An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma 1996; 13: 557–568.
- 41 Pineda JA, Aono M, Sheng H et al. Extracellular superoxide dismutase overexpression improves behavioral outcome from closed head injury in the mouse. J Neurotrauma 2001; 18: 625–634.
- 42 Ding Y, Yao B, Lai Q, McAllister JP. Impaired motor learning and diffuse axonal damage in motor and visual systems of the rat following traumatic brain injury. Neurol Res 2001; 23: 193–202.
- 43 Sanchez-Ramos J, Song S, Cardozo-Pelaez F et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000; 164: 247–256.
- 44 Woodbury D, Reynolds K, Black IB. Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 2002; 69: 908–917.
- 45 Yamaguchi S, Kuroda S, Kobayashi H et al. The effects of neuronal induction on gene expression profile in bone marrow stromal cells (BMSC)-a preliminary study using microarray analysis. Brain Res 2006; 1087: 15–27.
- 46 Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S. Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 2005; 105: 3793–3801.
- 47 Gao Q, Li Y, Chopp M. Bone marrow stromal cells increase astrocyte survival via upregulation of phosphoinositide 3-kinase/threonine protein kinase and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and stimulate astrocyte trophic factor gene expression after anaerobic insult. Neuroscience 2005; 136: 123–134.
- 48 Garcia R, Aguiar J, Alberti E, De La Cuetara K, Pavon N. Bone marrow stromal cells produce nerve growth factor and glial cell line-derived neurotrophic factors. Biochem Biophys Res Commun 2004; 316: 753–754.
- 49 Zhong C, Qin Z, Zhong CJ, Wang Y, Shen XY. Neuroprotective effects of bone marrow stromal cells on rat organotypic hippocampal slice culture model of cerebral ischemia. Neurosci Lett 2003; 342: 93–96.
- 50 Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G, Fischer I. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 2005; 1035: 73–85.
- 51 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: 687–691.
- 52 Povlishock JT. Pathobiology of traumatically induced axonal injury in animals and man. Ann Emerg Med 1993; 22: 980–986.
- 53 Buki A, Povlishock JT. All roads lead to disconnection? – Traumatic axonal injury revisited. Acta Neurochir (Wien) 2006; 148: 181–193; discussion 93–94.
- 54 Pike BR, Zhao X, Newcomb JK, Glenn CC, Anderson DK, Hayes RL. Stretch injury causes calpain and caspase-3 activation and necrotic and apoptotic cell death in septo-hippocampal cell cultures. J Neurotrauma 2000; 17: 283–298.
- 55 Maxwell WL, McCreath BJ, Graham DI, Gennarelli TA. Cytochemical evidence for redistribution of membrane pump calcium-ATPase and ecto-Ca-ATPase activity, and calcium influx in myelinated nerve fibres of the optic nerve after stretch injury. J Neurocytol 1995; 24: 925–942.
- 56 Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA. Current concepts: diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil 2001; 82: 1461–1471.
- 57 Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968–973.
- 58 Terada N, Hamazaki T, Oka M et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–545.
Citing Literature
