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    2017, Vol. 8 Issue (1) : 115-127     DOI: 10.14336/AD.2016.0610
Original Article |
Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients
Lin Yunpeng1, Luo Lan Lan2, Sun Jian1, Gao Weiwei1, Tian Ye1, Park Eugene3, Baker Andrew3, Chen Jieli4,5, Jiang Rongcai1,*, Zhang Jianning1,*
1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
2Department off Psychological Science, Tianjin Medical University General Hospital, Tianjin 300052, China
3Department of Traumatic Critical Care Unit, St. Michael’s Hospital, Toronto, Canada
4Department of Neurology, Henry Ford Hospital, Detroit, MI USA
5Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China
Download: PDF(1322 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

To investigate the changes of circulating endothelial progenitor cells (EPCs) and stromal cell-derived factor-1α (SDF-1α)/CXCR4 expression in patients with mild traumatic brain injury (TBI) and the correlation between EPC level and the prognosis of mild TBI. 72 TBI patients (57 mild TBI, 15 moderate TBI patients) and 25 healthy subjects (control) were included. The number of circulating EPCs, CD34+, and CD133+ cells and the percentage of CXCR4+ cells in each cell population at 1,4,7,14,21 days after TBI were counted by flow cytometer. SDF-1α levels in serum were detected by ELISA assay. The patients were divided into poor and good prognosis groups based on Extended Glasgow Outcome Scale and Activity of Daily Living Scale at 3 months after TBI. Correlation analysis between each detected index and prognosis of mild TBI was performed. Moderate TBI patients have higher levels of SDF-1α and CXCR4 expression than mild TBI patients (P < 0.05). The percentage of CXCR4+ EPCs at day 7 post-TBI was significantly higher in mild TBI patients with poor prognosis than the ones with good prognosis (P < 0.05). HAMA and HAMD scores in mild TBI patients were significantly lower than moderate TBI patients (P < 0.05) in early term. The percentage of CXCR4+ EPCs at day 7 after TBI was significantly correlated with the prognosis outcome at 3 months. The mobilization of circulating EPCs can be induced in mild TBI. The expression of CXCR4+ in EPCs at 7 days after TBI reflects the short-term prognosis of brain injury, and could be a potential biological marker for prognosis prediction of mild TBI.

Keywords traumatic brain injury      endothelial progenitor cells      C-X-C chemokine receptor type 4 (CXCR-4)      stromal derived factor-1 (SDF-1)     
Corresponding Authors: Jiang Rongcai,Zhang Jianning   
About author:

Both equally contribute to this manuscript.

Issue Date: 01 February 2017
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Lin Yunpeng
Luo Lan Lan
Sun Jian
Gao Weiwei
Tian Ye
Park Eugene
Baker Andrew
Chen Jieli
Jiang Rongcai
Zhang Jianning
Cite this article:   
Lin Yunpeng,Luo Lan Lan,Sun Jian, et al. Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients[J]. Aging and disease, 2017, 8(1): 115-127.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2016.0610     OR     http://www.aginganddisease.org/EN/Y2017/V8/I1/115
Figure 1.  A sample illustration of detecting the percentage of CXCR4+ cells in circulating EPCs. (A) Cells were first run on a forward and side scatter to select mononuclear cells. (B) The selected cells were then gated on FITC-CD34 and PE-CD133 to choose CD34+, CD133+ and double positive EPCs. (C) The percentages of CXCR4+ cells on each cell population (EPCs) were finally measured by APC-CXCR4 staining.
ItemMild TBI group
(n = 57)
Moderate TBI group
(n = 15)
P value
Gender [n (%)]0.793
 Male40 (70.18%)10 (66.67%)
 Female17 (29.82%)5 (33.33%)
Age (year)48.19±16.6341.80±19.580.283
Time interval between onset and hospital admission (hour)5.34±2.165.10±2.690.758
Hospital days13.87±7.1424.60±7.850.000*
GCS score at admission14.44±0.6010.47±0.920.000*
Open/closed TBI [n (%)]15 (26.3%)/42(73.7%)4 (26.7%)/11(73.3%)0.607
Injury causes [n (%)]
 Stumble12 (21.05%)0 (0%)0.052
 Violence14 (24.56%)3 (20%)0.711
 Motor vehicle accidents21 (36.84%)9 (60%)0.106
 High falls10 (17.54%)3 (20%)0.826
Table 1  Comparison of general data of TBI patients.
Figure 2.  Prognosis and mental state of TBI patients. (A) Moderate TBI significantly induces a worse prognosis after TBI compared to the mild TBI group at 3 and 6 months after TBI, identified by GOS-E, IADL and ADLS scores. (B) HAMA and HAMD scores were significantly increased in the moderate TBI group compared to mild TBI group (p < 0.05) at 3 and 6 months after TBI. There was no significant difference in HAMA and HAMD scores between 3 and 6 months after discharge in mild or moderate TBI patients, respectively.
Figure 3.  Number of CD34+, CD133+ and EPCs in the peripheral blood. (A) Number of circulating EPCs in mild and moderate traumatic brain injury (TBI) patients, showing a similar tendency of “from low to high”, peaked at 7 days and then gradually decreased and was significantly higher than that in the control group at 7 and 14 days after TBI (*p < 0.05). (B) Mild TBI patients were further divided into a good prognosis group (group A) and a poor prognosis group (group B). There was no significant difference in EPC number among group A, group B and moderate TBI group (P > 0.05). (C) CD34+ cell number in the peripheral blood of mild and moderate TBI patients was very high in the early stage after TBI and began to significantly decrease at 7 days after TBI, and was significantly higher than control group at 1, 4, 7 and 14 days after TBI (*p < 0.05). There was no significant difference in CD34+ cell number between mild and moderate TBI groups (p > 0.05). (D) CD133+ cell number in the peripheral blood of all TBI patients was also very high in the early stage after TBI and began to significantly decrease at 7 days after TBI, and was significantly higher than the control group at 1, 4, 7, 14 and 21 days after TBI (*p < 0.05). There was no significant difference in CD133+ cell number between mild and moderate TBI group (p > 0.05).
Figure 4.  Percentage of CXCR4+ cells on EPCs, CD34+ and CD133+ cells in TBI patients. (A, D, G) show the percentages of CXCR4+ cells in EPCs, CD34+ or CD133+ cells were significantly higher than the baseline level (control group; *p < 0.05) at early stage (within 14 days) after TBI and then gradually decreased in the following days. (B) The percentage of CXCR4+ cells in EPCs of mild TBI patients was significantly higher than that in the control group (*p < 0.05) at 1, 4, and 14 days after TBI. The percentage of CXCR4+ cells in EPCs in the mild TBI group was significantly lower than the moderate TBI group at 4, 7, 14, 21 days (#p < 0.05). (E, H) There was no significant difference between mild TBI and moderate TBI groups (P > 0.05) in circulating CD34+ and CD133+ cell expression. (C, F, I) Mild TBI patients were further divided into a good prognosis group (group A) and a poor prognosis group (group B). (C) The percentage of CXCR4+/EPC in group A was significantly lower than group B at 7 days after TBI (F = 11.375, *p = 0.002). (F) The percentage of CXCR4+/CD34+ cells in group A was significantly lower than group B at 7 days after TBI (F = 6.124, *p = 0.02). (I) The percentage of CXCR4+/CD133+ cells in group A was significantly lower than group B at 7 days after TBI (F = 7.435, *p = 0.011).
Figure 5.  Changes in serum SDF-1α level after TBI. (A) Serum SDF-1α levels in mild and moderate TBI groups were significantly increased at 1,4,7,14 and 21days after TBI compared to control group (*p < 0.05). SDF-1 was significantly higher in the moderate TBI group than the mild TBI group at 1 and 4 days after TBI (#p < 0.05). (B) Mild TBI patients were further divided into a good prognosis group (group A) and a poor prognosis group (group B). There was no statistical significance in SDF-1α levels between group A and B.
Figure 6.  Correlation analysis. (A) There is significant relationship between percentage of CXCR4+/EPCs (7 day after admission) in mild TBI patients (R= 0.518, p = 0.002) with the prognosis at 3 months after TBI. (B) There is significant correlation between percentage of CXCR4+/EPCs (7 day after admission) in all TBI patients (R= 0.605, p = 0.000) with the prognosis at 3rd month after TBI.
Concomitant variableRegression coefficientStandard errorWald valuepOR95% confidence interval
Lower
limit
Upper
limit
X10.1490.0773.7890.0521.1610.9991.350
X20.1080.0593.4070.0651.1140.9931.250
X30.1270.0604.4070.036*1.1351.0081.278
Constant-23.9639.2756.6750.0100.000
Table 2  Logistic regression analysis results of each factor that influences the prognosis of patients with mild traumatic brain injury
Figure 7.  Receiver operating characteristic (ROC) curve. ROC created based on the percentage of CXCR4+/EPCs at day 7 after admission and the prognosis of patients with mild TBI. The area under the AUC was 0.807 (95% CI = 0.656-0.958, critical value = 42.35%, p = 0.003).
GroupCritical valueArea under the curveStandard errorp95% confidence interval
Lower limitUpper limit
Mild TBI (n = 57)42.350.8070.0770.003*0.6560.958
Table 3  Parameters of receiver operating characteristic (ROC) curve created based on the percentage of CXCR4+ cells in EPCs at 7 days after admission and the prognosis of patients with mild TBI
Figure 8.  Correlation between the percentage of CXCR4+/EPCs and psychological state after TBI. (A) Figure shows significant correlation between the percentage of CXCR4+/EPCs at day 7 after TBI and the HAMA score at 3 months after discharge (R = 0.501, p = 0.003). (B) Figure shows significant relationship between the percentage of CXCR4+/EPCs at day 7 after TBI and the HAMD score at 3 months after discharge (R = 0.515, p = 0.002).
[1] Eramudugolla R, Bielak AA, Bunce D, Easteal S, Cherbuin N, Anstey KJ (2014). Long-term cognitive correlates of traumatic brain injury across adulthood and interactions with APOE genotype, sex, and age cohorts. J Int Neuropsychol Soc, 20: 444-54
[2] Falk AC, Alm A, Lindstrom V (2014). Has increased nursing competence in the ambulance services impacted on pre-hospital assessment and interventions in severe traumatic brain-injured patients? Scand J Trauma Resusc Emerg Med, 22: 20
[3] Pearson WS, Sugerman DE, McGuire LC, Coronado VG (20012). Emergency department visits for traumatic brain injury in older adults in the United States:2006-08. West J Emerg Med. 2012 Aug;13(3):289-93.
[4] Hou R, Moss-Morris R, Peveler R, et al (2012). When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury. J Neurol Neurosurg Psychiatry, 83:217-23.
[5] Wilkinson CW, Pagulayan KF, Petrie EC, Mayer CL, Colasurdo EA, Shofer JB, et al. (2012). High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol, 3: 11
[6] Miller NR, Yasen AL, Maynard LF, Chou LS, Howell DR, Christie AD (2014). Acute and longitudinal changes in motor cortex function following mild traumatic brain injury. Brain Inj, 28: 1270-6
[7] Tanriverdi F, Unluhizarci K, Kocyigit I, Tuna IS, Karaca Z, Durak AC, et al. (2008). Brief communication: pituitary volume and function in competing and retired male boxers. Ann Intern Med, 148: 827-31
[8] Friedrich EB, Werner C, Walenta K, Bohm M, Scheller B (2009). Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease. Basic Res Cardiol, 104: 613-20
[9] Zhang Y, Li Y, Wang S, Han Z, Huang X, Li S, et al. (2013). Transplantation of expanded endothelial colony-forming cells improved outcomes of traumatic brain injury in a mouse model. J Surg Res, 185: 441-9
[10] Liu L, Liu H, Jiao J, Liu H, Bergeron A, Dong JF, et al. (2007). Changes in circulating human endothelial progenitor cells after brain injury. J Neurotrauma, 24: 936-43
[11] Liu L, Wei H, Chen F, Wang J, Dong JF, Zhang J (2011). Endothelial progenitor cells correlate with clinical outcome of traumatic brain injury. Crit Care Med, 39: 1760-5
[12] Huang XT, Zhang YQ, Li SJ, Li SH, Tang Q, Wang ZT, et al. (2013). Intracerebroventricular transplantation of ex vivo expanded endothelial colony-forming cells restores blood-brain barrier integrity and promotes angiogenesis of mice with traumatic brain injury. J Neurotrauma, 30: 2080-8
[13] Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996). A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med, 184: 1101-9
[14] Wang YB, Liu YF, Lu XT, Yan FF, Wang B, Bai WW, et al. (2013). Rehmannia glutinosa extract activates endothelial progenitor cells in a rat model of myocardial infarction through a SDF-1 alpha/CXCR4 cascade. PLoS One, 8: e54303
[15] Fierro FA, Brenner S, Oelschlaegel U, Jacobi A, Knoth H, Ehninger G, et al. (2009). Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia. Leukemia, 23: 393-6
[16] Li LP, Kang JL, Xia W (2008). Effect of first, second, and third trimester placental factors on CD4, CCR5, and CXCR4 expression in human peripheral blood lymphocytes. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 33: 461-7
[17] Gonzalez FJ, Carvajal MJ, Leiva L, Juarez C, Blanca M, Santamaria LF (1997). Expression of the cutaneous lymphocyte-associated antigen in circulating T cells in drug-allergic reactions. Int Arch Allergy Immunol, 113: 345-7
[18] Banisadr G, Rostene W, Kitabgi P, Parsadaniantz SM (2005). Chemokines and brain functions. Curr Drug Targets Inflamm Allergy, 4: 387-99
[19] Petit I, Jin D, Rafii S (2007). The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol, 28: 299-307
[20] Li S, Wei M, Zhou Z, Wang B, Zhao X, Zhang J (2012). SDF-1alpha induces angiogenesis after traumatic brain injury. Brain Res, 1444: 76-86
[21] Ingebrigtsen T, Romner B, Kock-Jensen C (2000). Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries. The Scandinavian Neurotrauma Committee. J Trauma, 48:760-766.
[22] Lawton MP, Brody EM (1969). Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist, 9: 179-86
[23] Schretlen DJ, Shapiro AM (2003). A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry, 15: 341-9
[24] Gyoneva S, Ransohoff RM (2015). Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci, 36: 471-80
[25] Li Z, Wang B, Kan Z, Zhang B, Yang Z, Chen J, et al. (2012). Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats. J Neurotrauma, 29: 343-53
[26] Trop S, Tremblay ML, Bourdeau A (2008). Modulation of bone marrow-derived endothelial progenitor cell activity by protein tyrosine phosphatases. Trends Cardiovasc Med, 18: 180-6
[27] Banisadr G, Fontanges P, Haour F, Kitabgi P, Rostene W, Melik Parsadaniantz S (2002). Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons. Eur J Neurosci, 16: 1661-71
[28] Guyon A, Skrzydelsi D, Rovere C, Rostene W, Parsadaniantz SM, Nahon JL (2006). Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. J Neurochem, 96: 1540-50
[29] Banisadr G, Queraud-Lesaux F, Boutterin MC, Pelaprat D, Zalc B, Rostene W, et al. (2002). Distribution, cellular localization and functional role of CCR2 chemokine receptors in adult rat brain. J Neurochem, 81: 257-69
[30] Engelhardt B, Ransohoff RM (2012). Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol, 33: 579-89
[31] Proudfoot AE, Uguccioni M (2016). Modulation of Chemokine Responses: Synergy and Cooperativity.Front Immunol,7:183.
[32] Chen H, Xu X, Teng J, Cheng S, Bunjhoo H, Cao Y, Liu J, Xie J, Wang C, Xu Y, Xiong W (2016). CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response.Exp Ther Med,11(5):1865-1870
[33] Bachstetter AD, Zhou Z, Rowe RK, Xing B, Goulding DS, Conley AN, Sompol P, Meier S, Abisambra JF, Lifshitz J, Watterson DM, Van Eldik LJ (2016). MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.PLoS One,11(2):e0149451.
[34] Yang SH, Gangidine M, Pritts TA, Goodman MD, Lentsch AB (2013). Interleukin 6 mediates neuroinflammation and motor coordination deficits after mild traumatic brain injury and brief hypoxia in mice.Shock,40(6):471-5.
[35] Guyon A (2014). CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles. Front Cell Neurosci, 5: 115
[36] Mao W, Yi X, Qin J, Tian M, Jin G (2014). CXCL12 inhibits cortical neuron apoptosis by increasing the ratio of Bcl-2/Bax after traumatic brain injury. Int J Neurosci, 124: 281-90
[37] Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. (2004). Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med, 10: 858-64
[38] Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, et al. (2003). HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest, 112: 160-9
[39] Gonzalo JA, Lloyd CM, Peled A, Delaney T, Coyle AJ, Gutierrez-Ramos JC (2000). Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease. J Immunol, 165: 499-508
[1] Stephanie Plummer,Corinna Van den Heuvel,Emma Thornton,Frances Corrigan,Roberto Cappai. The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury[J]. A&D, 2016, 7(2): 163-179.
[2] Lanlan Luo,Yan Chai,Rongcai Jiang,Xin Chen,Tao Yan. Cortisol Supplement Combined with Psychotherapy and Citalopram Improves Depression Outcomes in Patients with Hypocortisolism after Traumatic Brain Injury[J]. A&D, 2015, 6(6): 418-425.
[3] Ben Waldau. Stem Cell Transplantation for Enhancement of Learning and Memory in Adult Neurocognitive Disorders[J]. A&D, 2010, 1(1): 60-71.
Viewed
Full text


Abstract

Cited

  Shared   
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: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd