Inflammatory events drive neural stem cell migration by elevating stromal-derived factor 1 alpha

  • Ziyun Jiang Joint Research Institute of Southeast University and Monash University, Suzhou 215123, China; Melbourne 500301, Australia.
  • Mingliang Tang Joint Research Institute of Southeast University and Monash University, Suzhou 215123, China; Melbourne 500301, Australia.
Keywords: Microglia, Oxygen-glucose deprivation, Neural stem cells, Migration


Background: Ischemic stroke is the most common cause of ischemia-related death globally. Brain injuries due to stroke and trauma are typically followed by inflammation reactions within the central nervous system (CNS). Neural stem cell (NSC)-based therapeutic strategies show great potential for treating stroke and ischemia-mediated brain injuries, and migration of NSCs is a critical step involved in NSC-based therapy.

Methods: In order to examine the effects of microglial activation upon ischemia and stroke on NSC behaviors, oxygen-glucose deprivation (OGD) in vitro model was established for mimicking in vivo stroke and ischemia pathological conditions in this study. By combining of enzyme-linked immunosorbent assay, migration assay, Western blot and immunostaining, we found that OGD insult induced microglial activation by releasing cytokines and chemokines.

Results: The conditioned media (CM) of OGD-treated groups impaired the proliferation and capability of neurosphere formation. Moreover, we found the stromal cell-derived factor 1α/CXC chemokine receptor 4 (CXCR4) pathway was an active player that facilitated the migration of NSCs, since a CXCR4 specific antagonist AMD3100 was able to impair NSC migration both in vitro and in vivo.

Conclusion: The current study presents a potential interaction between NSC behaviors and microglial activation underlying brain injuries, such as ischemia and stroke. More importantly, we reveal the underlying mechanisms of microglia-induced NSC migration under OGD conditions and it should be beneficial to stem cell-based therapies to treat acute brain injuries.


Download data is not yet available.


Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17(7):796-808.

Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K. Microglia provide neuroprotection after ischemia. FASEB J. 2006;20(6):714-6.

Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101(52):18117-22.

Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995;20(3):269-87.

Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57-69.

Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15(8):946-50.

Gliem M, Mausberg AK, Lee JI, Simiantonakis I, van Rooijen N, Hartung HP, et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann Neurol. 2012;71(6):743-52.

Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases. Curr Med Chem. 2007;14(11):1189-97.

Moon JB, Lee CH, Park CW, Cho JH, Hwang IK, Yoo KY, et al. Neuronal degeneration and microglial activation in the ischemic dentate gyrus of the gerbil. J Vet Med Sci. 2009;71(10):1381-6.

Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, et al. Generalized potential of adult neural stem cells. Science. 2000;288(5471):1660-3.

Aarum J, Sandberg K, Haeberlein SL, Persson MA. Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A. 2003;100(26):15983-8.

Bye N, Turnley AM, Morganti-Kossmann MC. Inflammatory regulators of redirected neural migration in the injured brain. Neurosignals. 2012;20(3):132-46.

Magge SN, Malik SZ, Royo NC, Chen HI, Yu L, Snyder EY, et al. Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors. J Neurosci Res. 2009;87(7):1547-55.

Zhang W, Smith C, Shapiro A, Monette R, Hutchison J, Stanimirovic D. Increased expression of bioactive chemokines in human cerebromicrovascular endothelial cells and astrocytes subjected to simulated ischemia in vitro. J Neuroimmunol. 1999;101(2):148-60.

Gaviria M, Haton H, Sandillon F, Privat A. A mouse model of acute ischemic spinal cord injury. J Neurotrauma. 2002;19(2):205-21.

Corti S, Locatelli F, Papadimitriou D, Donadoni C, Del Bo R, Crimi M, et al. Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. Hum Mol Genet. 2006;15(2):167-87.

Eyo U, Dailey ME. Effects of oxygen-glucose deprivation on microglial mobility and viability in developing mouse hippocampal tissues. Glia. 2012;60(11):1747-60.

Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci. 1999;19(5):1708-16.

Lee JC, Cho GS, Kim HJ, Lim JH, Oh YK, Nam W, et al. Accelerated cerebral ischemic injury by activated macrophages/microglia after lipopolysaccharide microinjection into rat corpus callosum. Glia. 2005;50(2):168-81.

Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A. 1998;95(26):15769-74.

Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496-500.

Giulian D, Corpuz M, Chapman S, Mansouri M, Robertson C. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res. 1993;36(6):681-93.

Giulian D, Vaca K, Corpuz M. Brain glia release factors with opposing actions upon neuronal survival. J Neurosci. 1993;13(1):29-37.

Polazzi E, Contestabile A. Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci. 2002;13(3):221-42.

Wang J, Li PT, Du H, Hou JC, Li WH, Pan YS, et al. Impact of paracrine signals from brain microvascular endothelial cells on microglial proliferation and migration. Brain Res Bull. 2011;86(1-2):53-9.

Jin F, Zhao L, Zhao HY, Guo SG, Feng J, Jiang XB, et al. Comparison between cells and cancer stem-like cells isolated from glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug resistance-associated protein genes. Neuroscience. 2008;154(2):541-50.

Suslov ON, Kukekov VG, Ignatova TN, Steindler DA. Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres. Proc Natl Acad Sci U S A. 2002;99(22):14506-11.

Lobo MVT, Alonso FJM, Redondo C, oacute, pez-Toledano MA, Caso E, et al. Cellular characterization of epidermal growth factor-expanded free-floating neurospheres.J Histochem Cytochem. 2003;51(1):89-103.

Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, et al. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells. 2009;27(4):980-7.

Liao H, Bu WY, Wang TH, Ahmed S, Xiao ZC. Tenascin-R plays a role in neuroprotection via its distinct domains that coordinate to modulate the microglia function. J Biol Chem. 2005;280(9):8316-23.

Morgan SC, Taylor DL, Pocock JM. Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3 kinase/Akt and delta-Notch signalling cascades. J Neurochem. 2004;90(1):89-101.

Carbajal KS, Schaumburg C, Strieter R, Kane J, Lane TE. Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc Natl Acad Sci U S A. 2010;107(24):11068-73.

Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, et al. Cell migration: integrating signals from front to back. Science. 2003;302(5651):1704-9.

Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, et al. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007;21(12):3219-30.

Won Y-W, Patel AN, Bull DA. Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. Biomaterials. 2014;35(21):5627-35.

Bagri A, Gurney T, He X, Zou Y-R, Littman DR, Tessier-Lavigne M, et al. The chemokine SDF1 regulates migration of dentate granule cells. Development. 2002;129(18):4249-60.

Ehtesham M, Mapara KY, Stevenson CB, Thompson RC. CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett. 2009;274(2):305-12.

Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998;95(16):9448-53.

Ratajczak MZ, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, Ratajczak J. The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia. 2006;20(11):1915-24.

Hatse S, Princen K, Bridger G, De Clercq E, Schols D. Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS lett. 2002;527(1-3):255-62.

How to Cite
JiangZ., & TangM. (2020). Inflammatory events drive neural stem cell migration by elevating stromal-derived factor 1 alpha. STEMedicine, 1(3), e59.
Research articles