Skip to main content
  • Implantation of Neural Stem Cells Carrying Galectin-1 Elicits Long-term Neuroprotection Against Traumatic Brain Injury in Mice

    Final Number:

    Ling Chen MD, PhD; Anthony K.F. Liou; Feng Zhang; Chen Jun

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Galectin-1 (gal-1) is a ß-galactoside-binding lectin that is normally expressed in the brain at low levels and upregulated after injury. Gal-1 is known to protect against ischemic brain injury. The present study investigates the protective effects of gal-1 against traumatic brain injury (TBI). Control neural stem cells (NE-4C) or cells carrying the secretory form of gal-1 (s-NE-4C) were implanted into the corpus callosum and striatum of adult mouse brains 1 hour after controlled cortical impact, a well-established model of TBI. Neurological performance and lesion volumes were assessed up to 35 days post-TBI. The potential mechanisms underlying gal-1-mediated protection were also investigated. s-NE-4C implantation led to more potent neuroprotection than NE-4C alone, as shown by reductions in neurological dysfunction, lesion size, and hippocampal CA3 neuronal death. Gal-1 treatment protected cultured oligodendrocyte progenitor cells against excitotoxicity and reduced the production of tumor necrosis factor-a and nitric oxide after lipopolysaccharide stimulation in microglial cell cultures.

    Methods: All animal experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee, and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

    Results: Generation of s-NE-4C cells and their fate after implantation into the brain.Neural stem cell transplantation attenuates behavioral deficits.Neural stem cell implantation reduces lesion size and hippocampal CA3 neuronal death.Neural stem cells attenuate oligodendrocyte precursor cell death and white matter injury.Gal-1 suppresses secretion of NO and TNF-a in activated microglia.

    Conclusions: Our novel findings suggest that implantation of neural stem cells carrying the secreted form of gal-1 provides potent neuroprotection against TBI by targeting gray matter, white matter, and microglial function.

    Patient Care: implantation of neural stem cells carrying the secreted form of gal-1 provides potent neuroprotection against TBI by targeting gray matter, white matter, and microglial function.

    Learning Objectives: s-NE-4C implantation reduced white matter injury and microglial activation after TBI in vivo

    References: 1. Wang, G. et al. HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3beta/PTEN/Akt axis. Proc. Natl. Acad. Sci. U. S. A. 112, 2853-2858 (2015). 2. Rosenfeld, J. V. et al. Early management of severe traumatic brain injury. Lancet 380, 1088-1098 (2012). 3. Kinnunen, K. M. et al. White matter damage and cognitive impairment after traumatic brain injury. Brain 134, 449-463 (2011). 4. Spitz, G., Maller, J. J., O'Sullivan, R. & Ponsford, J. L. White matter integrity following traumatic brain injury: the association with severity of injury and cognitive functioning. Brain Topogr. 26, 648-660 (2013). 5. Sharma, A. et al. Cell therapy attempted as a novel approach for chronic traumatic brain injury - a pilot study. Springerplus 4, 26 (2015). 6. De La Pena, I., Sanberg, P. R., Acosta, S., Lin, S. Z. & Borlongan, C. V. G-CSF as an adjunctive therapy with umbilical cord blood cell transplantation for traumatic brain injury. Cell Transplant. 24, 447-457 (2015). 7. Blaya, M. O., Tsoulfas, P., Bramlett, H. M. & Dietrich, W. D. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp. Neurol. 264, 67-81 (2015). 8. Drago, D. et al. The stem cell secretome and its role in brain repair. Biochimie 95, 2271-2285 (2013). 9. Pluchino, S. & Cossetti, C. How stem cells speak with host immune cells in inflammatory brain diseases. Glia 61, 1379-1401 (2013). 10. Hsieh, J. Y. et al. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One 8, e72604 (2013). 11. Sasaki, T., Hirabayashi, J., Manya, H., Kasai, K. & Endo, T. Galectin-1 induces astrocyte differentiation, which leads to production of brain-derived neurotrophic factor. Glycobiology 14, 357-363 (2004). 12. Mokarizadeh, A. et al. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol. Lett. 147, 47-54 (2012). 13. Sakaguchi, M. & Okano, H. Neural stem cells, adult neurogenesis, and galectin-1: from bench to bedside. Dev. Neurobiol. 72, 1059-1067 (2012). 14. Camby, I., Le Mercier, M., Lefranc, F. & Kiss, R. Galectin-1: a small protein with major functions. Glycobiology 16, 137R-157R (2006). 15. Seelenmeyer, C. et al. Cell surface counter receptors are essential components of the unconventional export machinery of galectin-1. J. Cell. Biol. 171, 373-381 (2005). 16. Sakaguchi, M. et al. A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells. Proc. Natl. Acad. Sci. U. S. A. 103, 7112-7117 (2006). 17. Starossom, S. C. et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity 37, 249-263 (2012). 18. Yamane, J. et al. Transplantation of human neural stem/progenitor cells overexpressing galectin-1 improves functional recovery from focal brain ischemia in the Mongolian gerbil. Mol. Brain 4, 35 (2011). 19. Ishibashi, S. et al. Galectin-1 regulates neurogenesis in the subventricular zone and promotes functional recovery after stroke. Exp. Neurol. 207, 302-313 (2007). 20. Qu, W. S. et al. Galectin-1 enhances astrocytic BDNF production and improves functional outcome in rats following ischemia. Neurochem. Res. 35, 1716-1724 (2010). 21. Ishibashi, S. et al. Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils. J. Neurosci. Res. 78, 215-223 (2004). 22. Wang, J. et al. Galectin-1-secreting neural stem cells elicit long-term neuroprotection against ischemic brain injury. Sci. Rep. 5, 9621 (2015). 23. Sakaguchi, M., Imaizumi, Y. & Okano, H. Expression and function of galectin-1 in adult neural stem cells. Cell Mol. Life Sci. 64, 1254-1258 (2007). 24. Qu, W. S. et al. Galectin-1 attenuates astrogliosis-associated injuries and improves recovery of rats following focal cerebral ischemia. J. Neurochem. 116, 217-226 (2011). 25. Shi, H. et al. Demyelination as a rational therapeutic target for ischemic or traumatic brain injury. Exp. Neurol. (2015). 26. Sharp, D. J. & Ham, T. E. Investigating white matter injury after mild traumatic brain injury. Curr. Opin. Neurol. 24, 558-563 (2011). 27. Horie, H. et al. Oxidized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral nerves after axotomy. J. Neurosci. 24, 1873-1880 (2004). 28. Quinta, H. R., Pasquini, J. M., Rabinovich, G. A. & Pasquini, L. A. Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury. Cell Death Differ. 21, 941-955 (2014). 29. Baldini, A. et al. Mapping on human and mouse chromosomes of the gene for the beta-galactoside-binding protein, an autocrine-negative growth factor. Genomics 15, 216-218 (1993). 30. Mao, H., Elkin, B. S., Genthikatti, V. V., Morrison, B., 3rd & Yang, K. H. Why is CA3 more vulnerable than CA1 in experimental models of controlled cortical impact-induced brain injury? J. Neurotrauma 30, 1521-1530 (2013). 31. Langston, R. F., Stevenson, C. H., Wilson, C. L., Saunders, I. & Wood, E. R. The role of hippocampal subregions in memory for stimulus associations. Behav. Brain Res. 215, 275-291 (2010). 32. Pu, H. et al. Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury. J. Cereb. Blood. Flow. Metab. 33, 1474-1484 (2013). 33. Outenreath, R. L. & Jones, A. L. Influence of an endogenous lectin substrate on cultured dorsal root ganglion cells. J. Neurocytol. 21, 788-795 (1992). 34. Rodriguez-Rodriguez, A., Egea-Guerrero, J. J., Murillo-Cabezas, F. & Carrillo-Vico, A. Oxidative stress in traumatic brain injury. Curr. Med. Chem. 21, 1201-1211 (2014). 35. Corps, K. N., Roth, T. L. & McGavern, D. B. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol. 72, 355-362 (2015). 36. Karve, I. P., Taylor, J. M. & Crack, P. J. The contribution of astrocytes and microglia to traumatic brain injury. Br. J. Pharmacol. (2015). 37. Demeter, K., Zadori, A., Agoston, V. A. & Madarasz, E. Studies on the use of NE-4C embryonic neuroectodermal stem cells for targeting brain tumour. Neurosci. Res. 53, 331-342 (2005). 38. Schlett, K. & Madarasz, E. Retinoic acid induced neural differentiation in a neuroectodermal cell line immortalized by p53 deficiency. J. Neurosci. Res. 47, 405-415 (1997). 39. Wu, C. et al. Polymeric vector-mediated gene transfection of MSCs for dual bioluminescent and MRI tracking in vivo. Biomaterials 35, 8249-8260 (2014). 40. Jing, Z. et al. Neuronal NAMPT is released after cerebral ischemia and protects against white matter injury. J. Cereb. Blood. Flow. Metab. 34, 1613-1621 (2014). 41. Lisak, R. P., Nedelkoska, L. & Benjamins, J. A. Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules. Glia 62, 751-762 (2014). 42. Zhang, W., Hu, X., Yang, W., Gao, Y. & Chen, J. Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti-inflammatory actions. Stroke 41, 2341-2347 (2010). 43. Chen, C. et al. Effect of HMGB1 on the paracrine action of EPC promotes post-ischemic neovascularization in mice. Stem Cells 32, 2679-2689 (2014). 44. Qin, L. et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453-462 (2007). 45. Hu, X. et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063-3070 (2012). 46. Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848-858 (2006). 47. Zhang, M. et al. Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. J. Neurosci. 34, 1903-1915 (2014). 48. Wang, G. et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J. Cereb. Blood. Flow. Metab. 33, 1864-1874 (2013). 49. Block, F. Global ischemia and behavioural deficits. Prog. Neurobiol. 58, 279-295 (1999).

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy