Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2018, Vol. 9 Issue (2) : 287-295     DOI: 10.14336/AD.2017.1112
Orginal Article |
SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke
Zhang Yu1, Zhang Hongxia2, Lin Siyang3, Chen Xudong3, Yao Yu4, Mao XiaoOu5, Shao Bei3, Zhuge Qichuan1,3,*, Jin Kunlin2,3,*
1Department of Neurosurgery, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
2Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Texas 76107, USA.
3Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
4Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
5Buck Institute for Age Research, Novato, California 94945, USA
Download: PDF(765 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Stromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptors CXCR4 and CXCR7 play important roles in brain repair after ischemic stroke, as SDF-1/ CXCR4/CXCR7 chemokine signaling is critical for recruiting stem cells to sites of ischemic injury. Upregulation of SDF-1/CXCR4/CXCR7 chemokine signaling in the ischemic regions has been well-documented in the animal models of ischemic stroke, but not in human ischemic brain. Here, we found that protein expression of SDF-1 and CXCR7, but not CXCR4, were significantly increased in the cortical peri-infarct regions (penumbra) after ischemic stroke in human, compared with adjacent normal tissues and control subjects. Double-label fluorescence immunohistochemistry shows that SDF-1 and CXCR4 proteins were expressed in neuronal cells and astrocytes in the normal brain tissue and peri-infarct regions. CXCR7 protein was also observed in neuronal cells and astrocytes in the normal cortical regions, but predominantly in astrocytes in the penumbra of ischemic brain. Our data suggest that ischemic stroke in human leads to an increase in the expression of SDF-1 and CXCR7, but not CXCR4, in the peri-infarct cerebral cortex. Our findings suggest that chemokine SFD-1 is expressed not only in animal models of stroke, but also in the human brain after an ischemic injury. In addition, unlike animals, CXCR7 may be the primary receptor of SDF-1 in human stroke brain.

Keywords SDF-1      CXCL12      CXCR4      CXCR7      chemokine      penumbra      ischemia      stroke      patient      human     
Corresponding Authors: Zhuge Qichuan,Jin Kunlin   
About author:

These authors contributed equally.

Issue Date: 01 April 2018
E-mail this article
E-mail Alert
Articles by authors
Zhang Yu
Zhang Hongxia
Lin Siyang
Chen Xudong
Yao Yu
Mao XiaoOu
Shao Bei
Zhuge Qichuan
Jin Kunlin
Cite this article:   
Zhang Yu,Zhang Hongxia,Lin Siyang, et al. SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke[J]. Aging and disease, 2018, 9(2): 287-295.
URL:     OR
Figure 1.  Expression pattern of SDF-1/CXCR4/CXCR7 in post-stroke human brain. A) Representative images show that SDF-1 expression in cerebral cortex of infarcted brain. Top panel: low magnification; Bottom panel: high magnification. B) CXCR7 immunocytochemistry in the peri-infarct region (penumbra) and adjacent normal tissue. C) CXCR4 immunocytochemistry in the cortical penumbra and adjacent normal tissue.
Figure 2.  Phenotypes of SDF-1-positive cells in the human ischemic brain. A-B) Confocal image of representative immunofluorescent staining for NeuN (A) or GFAP (B) (Alexa Fluor 594, red), SDF-1 (Alexa Fluor 488, green), nuclei (DAPI, blue), and merged image from adjacent normal regions of human ischemic stroke brain. C) Merged confocal images of double-label immunohistochemistry in the peri-infarct region (penumbra) of the human ischemic brain section using anti-GFAP (green) and anti-SDF-1 (red). D) Merged confocal images of double-label immunohistochemistry in the penumbra on the human ischemic brain using anti-NeuN (red) and anti-SDF-1 (green). DAPI (blue) was used for nuclei counterstains.
Figure 3.  Phenotypes of CXCR7-positive cells in the human ischemic brain. A) Merged confocal image of double-label immunohistochemistry on the normal region of the human ischemic brain section using anti-NeuN (red) and anti- CXCR7 (green). B) Merged confocal image of double-label immunohistochemistry on the normal region of the human ischemic brain section using anti-GFAP (red) and anti- CXCR7 (green). C) Double immunocytochemistry was performed on the ischemic brain sections in the penumbra using anti-GFAP (red) and anti-CXCR7 (green). The images were recorded using a 2-photon confocal microscope. D) Higher magnification view of merged confocal image in panel C. DAPI (blue) was used for nuclei counterstains.
Figure 4.  Phenotypes of CXCR4-expressed cells in the human ischemic brain. Double immunocytochemistry was performed on the ischemic brain sections and the images were recorded using a 2-photon confocal microscope. Representative images show that CXCR4 (green) was expressed in GFAP-positive astrocytes (red) in the normal region (A) and penumbra (C), and NeuN-positive neuronal cells (red) in the normal region (B) and penumbra (D) of human ischemic brain. DAPI (blue) was used for nuclei counterstains.
[1] Guyon A (2014). CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems. Front Cell Neurosci, 8:65.
[2] DeVries ME, Kelvin AA, Xu L, Ran L, Robinson J, Kelvin DJ (2006). Defining the origins and evolution of the chemokine/chemokine receptor system. J Immunol, 176:401-415.
[3] Wang Y, Huang J, Li Y, Yang GY (2012). Roles of chemokine CXCL12 and its receptors in ischemic stroke. Curr Drug Targets, 13:166-172.
[4] Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, et al. (2005). The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 280:35760-35766.
[5] Chen FM, Wu LA, Zhang M, Zhang R, Sun HH (2011). Homing of endogenous stem/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives. Biomaterials, 32:3189-3209.
[6] Dong F, Harvey J, Finan A, Weber K, Agarwal U, Penn MS (2012). Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction. Circulation, 126:314-324.
[7] Zhao HX, Wang XL, Wang YH, Wu Y, Li XY, Lv XP, et al. (2010). Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1alpha. Basic Res Cardiol, 105:109-118.
[8] Bonig H, Papayannopoulou T (2013). Hematopoietic stem cell mobilization: updated conceptual renditions. Leukemia, 27:24-31.
[9] Hill WD, Hess DC, Martin-Studdard A, Carothers JJ, Zheng J, Hale D, et al. (2004). SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol, 63:84-96.
[10] Schonemeier B, Schulz S, Hoellt V, Stumm R (2008). Enhanced expression of the CXCl12/SDF-1 chemokine receptor CXCR7 after cerebral ischemia in the rat brain. J Neuroimmunol, 198:39-45.
[11] Dar A, Kollet O, Lapidot T (2006). Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol, 34:967-975.
[12] Lanfranconi S, Locatelli F, Corti S, Candelise L, Comi GP, Baron PL, et al. (2011). Growth factors in ischemic stroke. J Cell Mol Med, 15:1645-1687.
[13] Wang Y, Deng Y, Zhou GQ (2008). 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.
[14] Bogoslovsky T, Spatz M, Chaudhry A, Maric D, Luby M, Frank J, et al. (2011). Stromal-derived factor-1[alpha] correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients. Stroke, 42:618-625.
[15] Petit I, Jin D, Rafii S (2007). The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol, 28:299-307.
[16] Dziembowska M, Tham TN, Lau P, Vitry S, Lazarini F, Dubois-Dalcq M (2005). A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia, 50:258-269.
[17] Dambly-Chaudiere C, Cubedo N, Ghysen A (2007). Control of cell migration in the development of the posterior lateral line: antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev Biol, 7:23.
[18] Liu P, Xiang JW, Jin SX (2015). Serum CXCL12 levels are associated with stroke severity and lesion volumes in stroke patients. Neurol Res, 37:853-858.
[19] Duan XX, Zhang GP, Wang XB, Yu H, Wu JL, Liu KZ, et al. (2015). The diagnostic and prognostic value of serum CXCL12 levels in patients with ischemic stroke. Neurol Sci, 36:2227-2234.
[20] Tavakolian Ferdousie V, Mohammadi M, Hassanshahi G, Khorramdelazad H, Khanamani Falahati-Pour S, Mirzaei M, et al. (2017). Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion. Int J Cardiol, 233:23-28.
[21] Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, et al. (2006). Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A, 103:13198-13202.
[22] Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, et al. (2003). Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci, 24:171-189.
[23] Zhang H, Sun F, Wang J, Xie L, Yang C, Pan M, et al. (2017). Combining Injectable Plasma Scaffold with Mesenchymal Stem/Stromal Cells for Repairing Infarct Cavity after Ischemic Stroke. Aging Dis, 8:203-214.
[24] Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB (2011). The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol, 95:213-228.
[25] Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, et al. (2002). A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci, 22:5865-5878.
[26] Chang YC, Shyu WC, Lin SZ, Li H (2007). Regenerative therapy for stroke. Cell Transplant, 16:171-181.
[27] Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, et al. (2007). Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab, 27:6-13.
[28] Mocco J, Afzal A, Ansari S, Wolfe A, Caldwell K, Connolly ES, et al. (2014). SDF1-a facilitates Lin-/Sca1+ cell homing following murine experimental cerebral ischemia. PLoS One, 9:e85615.
[29] Thomas MN, Kalnins A, Andrassy M, Wagner A, Klussmann S, Rentsch M, et al. (2015). SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy. Transpl Int, 28:1426-1435.
[30] Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, et al. (2006). Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells, 24:739-747.
[31] Gojska-Grymajlo A, Nyka WM, Zielinski M, Jakubowski Z (2012). CD34/CXCR4 stem cell dynamics in acute stroke patients. Folia Neuropathol, 50:140-146.
[32] Schonemeier B, Kolodziej A, Schulz S, Jacobs S, Hoellt V, Stumm R (2008). Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain. J Comp Neurol, 510:207-220.
[33] Lin Y, Luo LL, Sun J, Gao W, Tian Y, Park E, et al. (2017). Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients. Aging Dis, 8:115-127.
[34] Odemis V, Boosmann K, Heinen A, Kury P, Engele J (2010). CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. J Cell Sci, 123:1081-1088.
[35] Bonavia R, Bajetto A, Barbero S, Pirani P, Florio T, Schettini G (2003). Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation. Toxicol Lett, 139:181-189.
[36] Wang R, Li J, Duan Y, Tao Z, Zhao H, Luo Y (2017). Effects of Erythropoietin on Gliogenesis during Cerebral Ischemic/Reperfusion Recovery in Adult Mice. Aging Dis, 8:410-419.
[1] Jianji Xu,Yunjin Zang,Dongjie Liu,Tongwang Yang,Jieling Wang,Yanjun Wang,Xiaoni Liu,Dexi Chen. DRAM is Involved in Hypoxia/Ischemia-Induced Autophagic Apoptosis in Hepatocytes[J]. Aging and disease, 2019, 10(1): 82-93.
[2] Dong Liu,Liqun Xu,Xiaoyan Zhang,Changhong Shi,Shubin Qiao,Zhiqiang Ma,Jiansong Yuan. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury[J]. Aging and disease, 2019, 10(1): 116-133.
[3] Yang Hua,Lingyun Jia,Yingqi Xing,Pinjing Hui,Xuan Meng,Delin Yu,Xiaofang Pan,Yalan Fang,Binbin Song,Chunxia Wu,Chunmei Zhang,Xiufang Sui,Youhe Jin,Jingfen Zhang,Jianwei Li,Ling Wang,Yuming Mu,Jingxin Zhong,Yuhong Zhu,Heng Zhang,Xiaoyu Cai. Distribution Pattern of Atherosclerotic Stenosis in Chinese Patients with Stroke: A Multicenter Registry Study[J]. Aging and disease, 2019, 10(1): 62-70.
[4] Wanying Duan, Yuehua Pu, Haiyan Liu, Jing Jing, Yuesong Pan, Xinying Zou, Yilong Wang, Xingquan Zhao, Chunxue Wang, Yongjun Wang, Ka Sing Lawrence Wong, Ling Wei, Liping Liu, . Association between Leukoaraiosis and Symptomatic Intracranial Large Artery Stenoses and Occlusions: the Chinese Intracranial Atherosclerosis (CICAS) Study[J]. Aging and disease, 2018, 9(6): 1074-1083.
[5] Vinicius Alota Ignacio Pereira, Fabio Augusto Barbieri, Alessandro Moura Zagatto, Paulo Cezar Rocha dos Santos, Lucas Simieli, Ricardo Augusto Barbieri, Felipe Pivetta Carpes, Lilian Teresa Bucken Gobbi. Muscle Fatigue Does Not Change the Effects on Lower Limbs Strength Caused by Aging and Parkinson’s Disease[J]. Aging and disease, 2018, 9(6): 988-998.
[6] Fan Liu, Jianfei Lu, Anatol Manaenko, Junjia Tang, Qin Hu. Mitochondria in Ischemic Stroke: New Insight and Implications[J]. Aging and disease, 2018, 9(5): 924-937.
[7] Shuzhen Zhu,Xiaoya Gao,Kaibin Huang,Yong Gu,Yafang Hu,Yongming Wu,Zhong Ji,Qing Wang,Suyue Pan. Glibenclamide Enhances the Therapeutic Benefits of Early Hypothermia after Severe Stroke in Rats[J]. A&D, 2018, 9(4): 685-695.
[8] Jun Zhang,Kaiyin Liu,Omar Elmadhoun,Xunming Ji,Yunxia Duan,Jingfei Shi,Xiaoduo He,Xiangrong Liu,Di Wu,Ruiwen Che,Xiaokun Geng,Yuchuan Ding. Synergistically Induced Hypothermia and Enhanced Neuroprotection by Pharmacological and Physical Approaches in Stroke[J]. A&D, 2018, 9(4): 578-589.
[9] Tao Yan,Poornima Venkat,Michael Chopp,Alex Zacharek,Peng Yu,Ruizhuo Ning,Xiaoxi Qiao,Mark R. Kelley,Jieli Chen. APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats[J]. A&D, 2018, 9(3): 453-466.
[10] Zheng Zhang,Linlei Zhang,Yuchuan Ding,Zhao Han,Xunming Ji. Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence[J]. A&D, 2018, 9(3): 507-522.
[11] Xiangrong Liu,Shaohong Wen,Shunying Zhao,Feng Yan,Shangfeng Zhao,Di Wu,Xunming Ji. Mild Therapeutic Hypothermia Protects the Brain from Ischemia/Reperfusion Injury through Upregulation of iASPP[J]. A&D, 2018, 9(3): 401-411.
[12] Qi-Wen Deng,Shuo Li,Huan Wang,Leix Lei,Han-Qing Zhang,Zheng-Tian Gu,Fang-Lan Xing,Fu-Ling Yan. The Short-term Prognostic Value of the Triglyceride-to-high-density Lipoprotein Cholesterol Ratio in Acute Ischemic Stroke[J]. A&D, 2018, 9(3): 498-506.
[13] Can Zhang,Nicole R. Brandon,Kerryann Koper,Pei Tang,Yan Xu,Huanyu Dou. Invasion of Peripheral Immune Cells into Brain Parenchyma after Cardiac Arrest and Resuscitation[J]. A&D, 2018, 9(3): 412-425.
[14] Yuanyuan Ran,Zongjian Liu,Shuo Huang,Jiamei Shen,Fengwu Li,Wenxiu Zhang,Chen Chen,Xiaokun Geng,Zhili Ji,Huishan Du,Xiaoming Hu. Splenectomy Fails to Provide Long-Term Protection Against Ischemic Stroke[J]. A&D, 2018, 9(3): 467-479.
[15] Han Ziping, Zhao Haiping, Tao Zhen, Wang Rongliang, Fan Zhibin, Luo Yumin, Luo Yinghao, Ji Xunming. TOPK Promotes Microglia/Macrophage Polarization towards M2 Phenotype via Inhibition of HDAC1 and HDAC2 Activity after Transient Cerebral Ischemia[J]. Aging and disease, 2018, 9(2): 235-248.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd