Abstract
Circulating progenitor cells and stromal-derived factor-1alpha (SDF-1α) have been suggested to participate in tissue repair following ischemic injury. However, the predictive role of circulating CD133+CD34+ progenitors and plasma SDF-1α in ischemic stroke (IS) patients remains unknown. In this study, we recruited 95 acute IS patients, 40 at-risk subjects and 30 normal subjects. The NIH stroke scale (NIHSS), infarct volume and carotid intima-media thickness (IMT) were determined at day 1 and the modified rankin scale (mRS) of functional outcome was assessed at day 21. The levels of circulating CD133+CD34+ cells and plasma SDF-1α were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our data showed that: 1) The levels of CD133+CD34+ cells were lower in at-risk subjects and IS patients at admission (day 1) when compared to normal controls. 2) The day 1 level of CD133+CD34+ cells varied in IS subgroups and inversely correlated with NIHSS and carotid IMT. The level of SDF-1α inversely correlated with NIHSS and infarct volume. 3) The increment rates of circulating CD133+CD34+ cells and plasma SDF-1α within the first week were correlated. 4) Patients with a higher level of CD133+CD34+ cells at day 7 had a low mRS. The increase rate of CD133+CD34+ cells in the first week was inversely associated with mRS. In conclusion, our findings demonstrate that the circulating CD133+CD34+ progenitor cells and plasma SDF-1α can be used as predictive parameters for IS severity and outcome.
Keywords: progenitor cell, CD133+CD34+ cells, SDF-1α, ischemic stroke
Introduction
Ischemic stroke (IS) is a devastating disease and the fourth leading cause of death in the United States. However, the biomarkers for prediction of IS severity and outcome are lacking because of its complex pathogenesis and pathophysiology. Endothelial injury is implicated in the onset and progression of IS 1. Previous studies have suggested that circulating progenitor cells play pivotal roles in promoting endothelium repair and in maintaining vascular homeostasis 2, 3. Circulating CD133+CD34+ progenitors have been shown to participate in endothelial recovery after stroke onset 4. The level of circulating CD133+CD34+ progenitors have been reported to negatively associate with the level of neuroinflammatory marker in early IS patients. Nevertheless, there is no study directly addressing the potential of circulating CD133+ CD34+ progenitors in predicting the functional severity and clinical outcome of IS patients.
Stromal-derived factor-1alpha (SDF-1α) is recognized as one of the important chemokines participating in the process of tissue repair following ischemic injury 5. The capacity of SDF-1α in mobilizing progenitors from bone marrow into circulation has been well documented in previous studies 6, 7. A recent study in IS patients showed that plasma SDF-1α positively correlates with the level of circulating CD133+KDR+ cells 8. However, there is no study investigating the correlation of plasma SDF-1α with circulating CD133+CD34+ cells. Whether the level of SDF-1α could be used as a surrogate marker for IS remains unclear.
The aim of the present study was to determine the perspective of circulating CD133+CD34+ progenitor cells and plasma SDF-1α as predictive parameters for IS.
Materials and Methods
Study Subjects and Enrollment Criteria
This study enrolled 95 acute IS patients, 40 at-risk subjects and 30 normal subjects. Diagnosis of acute IS was made according to the standards established by the World Health Organization (WHO) 9. All patients admitted to the hospital within 72 hrs after stroke symptom onset were confirmed with cranial magnetic resonance imaging (MRI). Medical history recording, blood sample collection, and conventional exams such as 12-lead ECG, chest radiography, and carotid ultrasound were performed at admission (day 1). IS patients were classified into four subgroups: small artery occlusion (SAO), large artery atherosclerosis (LAA), cardioembolism (CE), and undetermined cause (UE), based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria 10. The age-matched at-risk subjects were recruited from subjects with stroke risk factors such as hypertension, diabetes, smoking and alcohol consumption. The normal control healthy subjects also completed health examinations including brain MRI, carotid ultrasound, blood tests, etc. The general characteristics of all study subjects are summarized in Table 1.
Table 1.
General characteristics in normal controls, at-risk subjects and stroke patients.
| Normal controls (n = 30) | At-risk Subjects (n = 40) | Stroke patients (n = 95) | |
|---|---|---|---|
| Demographics | |||
| Age (yr) | 67.43 ± 1.53 | 67.75 ± 1.54 | 68.9 ± 1.08 |
| Gender, % male (n) | 43.3 (13) | 45 (18) | 47.4 (45) |
| Risk factors | |||
| Hypertension, % (n) | ---- | 57.5 (23) | 62.1 (59) |
| Diabetes, % (n) | ---- | 27.5 (11) | 28.42 (27) |
| Smoking, % (n) | ---- | 10 (4) | 11.57 (11) |
| Alcohol consumption, % (n) | 3.33 (1) | 12.5 (5) | 13.68 (13) |
| Stroke history, % (n) | ---- | 20 (8) | 17.89 (17) |
| Blood pressures | |||
| SBP (mmHg) | 109.6 ± 1.65 | 139.84 ± 2.86 * | 144.6 ± 1.96 * |
| DBP (mmHg) | 66.34 ± 1.14 | 83.5 ± 1.5 * | 85.02 ± 1.4 * |
| Plasma lipids | |||
| TC (mmol/l) | 4.46 ± 0.11 | 4.52 ± 0.15 | 4.68 ± 0.08 |
| TG (mmol/l) | 1.25 ± 0.07 | 1.53 ± 0.11 * | 1.72 ± 0.09 * |
| HDL (mmol/l) | 1.17 ± 0.06 | 1.18 ± 0.06 | 1.22 ± 0.01 |
| LDL (mmol/l) | 2.42 ± 0.07 | 2.89 ± 0.15 * | 2.96 ± 0.07 * |
| Ultrasound parameters | |||
| IMT (mm) | 0.08 ±0.002 | 0.12±0.005 * | 0.12±0.003 * |
| Carotid atherosclerosis, % (n) | 0.033 (1) | 70 (21) * | 66.31 (66) * |
| Plaque, % (n) | 0.066 (2) | 42.5 (17) * | 64.21 (61) * |
| Stroke subgroups | |||
| NIHSS ≥ 7, % (n) | ---- | ---- | 45.3 (43) |
| LAA, % (n) | ---- | ---- | 31.6 (30) |
| SAO, % (n) | ---- | ---- | 34.7 (33) |
| CE, % (n) | ---- | ---- | 18.9 (18) |
| UE, % (n) | ---- | ---- | 14.7 (14) |
Results were expressed as means ± SEM.
P< 0.05, vs. normal controls; Abbreviations: LAA, large artery atherosclerosis; SAO, small artery occlusion; CE, cardioembolism; UE, undetermined cause; SBP, systolic blood pressure; DBP, diastolic blood pressure ; TC, total cholesterol; TG, triglyceride; HDL, high density lipoprotein; LDL, Low density lipoprotein ; IMT, intima-media thickness.
Exclusion criteria of subjects for the study included any of the situations: 1) infectious disease in a previous month, 2) autoimmune or peripheral vascular disease or cancer histories, 3) liver and kidney failure, 4) severe cardiac dysfunction, 5) cerebral infarction or hemorrhage histories (less than 3 months before the recruitment), 6) medications for lipid control or inflammation suppression or immunosuppression.
The research proposal was approved by the ethics committee in the Affiliated Hospital of Guangdong Medical College. Written informed consent was obtained from each participator.
Assessment of Neurological Impairment and Recovery
Acute neurological impairment and short-term outcome were evaluated by using NIH stroke scale (NIHSS) on day 1 11 and modified rankin scale (mRS) on day 21 12, respectively. Patients with NIHSS score ≥ 7 and < 7 were assigned into the different groups representing the severity of neurological impairment. The outcome was defined as “good” when mRS was ≤ 2 and as “poor” outcome when mRS was > 2.
Lesion Volume Measured by Brain MRI
Brain MRI was performed using a 1.5T clinical system (Philips Medical Systems). The lesion volume was measured by using diffusion-weighted imaging (DWI) as previously described 13. Briefly, the DWI was done by using a multi-slice, single-shot spin-echo EPI sequence. Typical sequence parameters were echo time of 118 msec, matrix size of 128 × 128, filed view of 260 × 260, and 7-mm slice thickness, with no gap between slices and with a set of 20 axial slices covering the whole brain. The volume was calculated by the summation of the slice thickness multiply the total lesion area. The MR diffusion sequence at b=1000 was run for 3 times, with diffusion gradients applied in each of the x, y, and z directions. To minimize the effects of diffusion anisotropy, an average of all 3 diffusion directions was calculated to give the trace of the diffusion tensor.
Intima-media Thickness, Plaque and Stenosis of Intracranial Artery Determined by Ultrasonography
The intima-media thickness (IMT) of carotid artery was measured through a standard B-mode ultrasound examination with the use of a grey scale high-resolution color Doppler ultrasound (ATL HDI 5000 scanner Philips, ATL ultrasound, Bothell, WA, USA) equipped with 5–12-MHz linear transducer as previously described 14. All procedures were performed on both sides of two longitudinal images of each internal carotid artery by the same operator. The carotid IMT was determined by measuring the distance between the lumen-intima and media-adventia border of the vascular wall. The most distal 1 cm segments (just proximal to the bulbar dilatation) of both common carotid arteries were scanned on longitudinal plane. The average of two IMT values from each side was used to calculate the mean IMT.
Carotid plaque was detected by using an ultrasonograph method 15. Ib brief, soft plaque was characterized by irregular plaque morphology, uneven low or moderate echo, smooth and continuous surface. Hard plaque was recognized based on rugged plaque, strong echo, and some with acoustic shadow. Mixed plaque included both soft and hard plaque elements. Soft and mixed plaques were unstable plaques. Carotid stenosis and brain artery stenosis were defined according to the criteria set by American College of Radiology Ultrasound Session 16 and the standard method 17.
All assessments and measurements were performed by a trained neurologist who was blinded to the patient's group and goals of analyses.
Flow Cytometric Analysis of Circulating CD133+CD34+ Progenitor Cells
Peripheral blood (2 ml) was collected from patients at days 1 and 7 after admission, or from at-risk subjects or normal subjects on the examination day. The level of circulating CD133+CD34+ progenitors were determined by flow cytometry as previously described 8, 18. In brief, the mononuclear cells were isolated from peripheral blood by gradient density centrifugation, then incubated with 10 μl PE-conjugated anti-human CD133 (Miltenyl Biotech, USA), and 10 μl FITC-conjugated anti-human CD34 (eBioscience, USA) antibodies for 30 min at 4°C in the dark. Isot ype matched (IgG) nonspecific antibodies (eBioscience, USA) served as negative controls. After incubation, labeled cells were washed and resuspended with 100 μl of phosphate-buffered saline (PBS) for flow cytometric analysis (Coulter Epics XL_MCL flow cytometer; Beckman Coulter). The flow cytometer was set to acquire 100,000 events/sample. As shown in Fig 1, the mononuclear cells were gated (P1). The cells within the gate were used for CD133 and CD34 expressing analysis. CD133+CD34+ cells were shown in the upper-right area (Q2). The level of circulating CD133+CD34+ progenitor cells was expressed as percentage of total mononuclear cells in each sample. The change rate of CD133+CD34+ cells from days 1 to 7 was calculated as: Δ CD133+CD34+ cells (%)= (CD133+CD34+ cells D7 - CD133+CD34+ cells D1 )/ CD133+CD34+ cells D1 × 100%.
Figure 1. Flow cytometry analysis of circulating CD133+CD34+ progenitors.
A, the mononuclear cell population was identified in forward and side scatter plots and gated (P1). B, the cells within the gate were used for CD133 and CD34 expressing analysis. CD133+CD34+ cells were shown in the upper-right area (Q2).
Enzyme-linked Immunosorbent Assay of Plasma SDF-1α
The level of plasma SDF-1α was measured by enzyme-linked immunosorbent assay(ELISA). Briefly, plasma was centrifuged at 1000 g for 10 min. The supernatant was collected as platelet-poor plasma (PPP). The SDF-1α level in the PPP was detected by using human CXCL12/SDF-1α ELISA kit (USCN lnc., USA). The change rate of SDF-1α from day 1 to 7 was calculated as Δ SDF-1α (%) = (SDF-1α D7 - SDF-1α D1 )/ SDF-1α D1 × 100%.
Statistical Analysis
Data was expressed as mean ± SEM. Comparisons for two groups were performed by Student's t-test. Multiple comparisons were performed by one- or two-way ANOVA. Comparisons for categorical characteristics were conducted by Chi-square test. Correlation between two variables was analyzed using the Spearman's rank correlation test. Multiple linear regression analysis was used for identifying the main impact factors of the mRS at day 21. SPSS software version 17.0 was used. For all tests, a P< 0.05 was considered statistically significant.
Results
General Characteristics of Normal Controls, At-risk Subjects and Stroke Patients
As shown in Table 1, there was no significant difference in age, gender, total cholesterol (TC), and high density lipoprotein (HDL) among the three groups. The diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG) and low density lipoprotein (LDL) were remarkably higher in IS patients and at-risk subjects compared with those in normal controls.
The Level of Circulating CD133+CD34+ Progenitors Was Reduced in IS Patients and At-risk Subjects, and Varied in Different IS Subgroups
The level of circulating CD133+CD34+ cells at day 1 was significantly lower in IS patients and at-risk subjects than that in normal controls. In addition, the level of circulating CD133+CD34+ cells was higher in the IS group when compared with the at-risk group (p < 0.05, n= 30-95/group; Fig 2-A). This data suggested that acute ischemic stroke could induce the release of progenitors from bone marrow into circulation. Moreover, IS subgroups displayed a variety in the level of CD133+CD34+ cells. Patients with LAA had the lowest level of CD133+CD34+ cells. The CD133+CD34+ cell levels were similar in CE and UE groups, but they were lower than that in SAO group (p < 0.05, n= 14-33/group; Fig 2-B).
Fig 2. The level of circulating CD133+CD34+ progenitors was reduced in IS and at-risk subjects, varied in different IS subgroups, low in IS with carotid plaque, and inversely correlated with carotid remodeling.
A, the day 1 level of CD133+CD34+ cells in normal controls, at-risk subjects and acute IS patients. B, the day 1 level of CD133+CD34+ cells in four stroke subgroups. C, the day 1 level of CD133+CD34+ cells in the patients with (w/) and without (w/o) carotid plaque (CP). D, the correlation between CD133+CD34+ cell level at day 1 and IMT in acute IS patients. Data was expressed as: mean ± SEM.
The Level of Circulating CD133+CD34+ Progenitors Was Low in IS Patients with Carotid Plaque and Was Inversely Correlated with Carotid Remodeling
According to the results of carotid ultrasonography, the stroke patients and at-risk subjects had significantly higher rates of carotid atherosclerosis and plaque, and a higher carotid IMT value when compared to those in normal controls (Tables 1 and 2). Among the stroke patients, those with carotid plaque (CP) had a lower level of CD133+CD34+ progenitors than those without CP (P < 0.05, n=34-61/group; Fig 2-C). In addition, with the spearman's rank correlation analysis, an inverse correlation was found between the level of circulating CD133+CD34+ cells and the carotid IMT value (r= - 0.35, p < 0.01; Fig 2-D).
Table 2.
Comparison of artery lesion in different stroke subgroups.
| SAO (n=33) | LAA (n=30) | CE (n=18) | UE (n=14) | |
|---|---|---|---|---|
| Atherosclerosis , % (n) | 51.51 (17) | 100 (30) * | 55.55 (10) | 78.57 (11) |
| Unstable plaque, % (n) | 12.12 (4) | 50 (15) * | 0 | 35.71(5) |
| Artery stenosis, % (n) | 0 | 100 (30) * | 0 | 28.57 (4) |
P<0.05, vs. SAO or CE or UE. Abbreviations: LAA, large artery atherosclerosis; SAO, small artery occlusion; CE, cardioembolism; UE, undetermined cause. Unstable plaque including soft plaque and mixed plaque.
The Level of Plasma SDF-1α Negatively Correlated with Lesion Volume and NIHSS in Acute IS
The correlations between plasma SDF-1α and NIHSS or stroke volume was assessed by Spearman's rank test. The results demonstrated that the acute lesion volume inversely correlated with plasma levels of SDF-1α on both days 1 and 7 (day 1: r= - 0.36; day 7: r= - 0.63, p < 0.01; Fig 3-A-B), and the NIHSS inversely correlated with plasma SDF-1α level on day 1 (r= - 0.31, p < 0.01; Fig 3-C).
Fig 3. The plasma concentration of SDF-1α negatively correlated with the infarct volume and NIHSS in acute IS patients.
A-B, the plasma levels of SDF-1α at both days 1 and 7 negatively correlated with the stroke volume. C. the plasma levels of SDF-1α at day 1 inversely correlated with NIHSS. Data was expressed as: mean ± SEM.
The Day 1 Level of Circulating CD133+CD34+ Progenitors Was Associated with NIHSS, and the Day 7 level and Increment Rate of CD133+CD34+ Progenitors Could be Used as a Predictor for Short-term Outcome
The level of circulating CD133+CD34+ cells at day 1 inversely correlated with NIHSS score (r= - 0.658, p < 0.01; Fig 4-A). Consistently, patients in the moderate neurological deficit group (NIHSS ≥7) had a lower level of CD133+CD34+ cells than that in the mild neurological deficit group (NIHSS < 7) (P < 0.05, n= 43-52/group; Fig 4-B). These data suggest that the level of circulating CD133+CD34+ cells on day 1 could reflect the stroke severity in acute phase. In addition, we found there was no significant difference of the levels of CD133+CD34+ cells on day 1 between stroke patients with good outcome (mRS ≤ 2) and those with poor outcome (mRS > 2) (p > 0.05, n= 47-48/group). Interestingly, the level of CD133+CD34+ cells on day 7 was significantly higher in the good outcome group as compared to those in the poor outcome group (p < 0.05, n= 47-48/group; Fig 4-C). Therefore, we further analyzed the association between day 1 CD133+CD34+ cell level (CD133+CD34+ cells D1), day 7 CD133+CD34+ cell level (CD133+CD34+ cells D7), the CD133+CD34+ cell change rate (ΔCD133+CD34+ cells) and the good outcome using multiple linear regression analysis. We found that CD133+CD34+ cells D7 and ΔCD133+CD34+ cells were significant predictors of a better short-term outcome on day 21 after acute IS (Table 3).
Fig 4. The level of circulating CD133+CD34+ cells correlated with NIHSS and predicts the IS prognosis.
A, correlation between CD133+CD34+ cell level on day 1 and NIHSS on admission in stroke patients. B, the day 1 level of CD133+CD34+ cells was much lower in patients with NIHSS ≥ 7 than that in patients with NIHSS < 7. C, the patients with a higher CD133+CD34+ level on day 7 after admission had a better outcome (mRS ≤ 2) on day 21. Data was expressed as: mean ± SEM.
Table 3.
Multiple linear regression analysis of predictors for mRS ≤ 2 on day 21 after admission.
| Model | B | SE | Beta | t | P |
|---|---|---|---|---|---|
| CD133+CD34+ cells D1 | 1.387 | 1.262 | 0.268 | 1.099 | 0.275 |
| CD133+CD34+ cells D7 | −1.9 | 0.954 | −0.408 | −1.991 | 0.049 |
| Δ CD133+CD34+ cells (%) | −0.451 | 0.139 | −0.423 | −3.242 | 0.002 |
The Increment rates of Circulating CD133+CD34+ Progenitors and Plasma SDF-1α were Positively Correlated in Acute IS
As shown in Fig 5-A, the day 1 level of plasma SDF-1α (ng/ml) was significantly higher in IS patients as compared to normal controls (P < 0.05, n=30-95/group), and the level of SDF-1α on day 7 was higher than that on day 1 in IS patients (P < 0.01, n=95/group). From day 1 to 7, the change rates of SDF-1α (ΔSDF-1α) and CD133+CD34+ cells (ΔCD133+CD34+ cells) were strongly correlated (r = 0.691, p < 0.01, Fig 5-B).
Fig 5. The plasma concentration of SDF-1α was increased following ischemic stroke, and its increment rate correlated with the level of circulating CD133+CD34+ cells.
A, the level of SDF-1α was increased in stroke patients over the time. B, the increment rate of SDF-1α correlated with the increment rate of CD133+CD34+ cells. Data was expressed as: mean ± SEM.
Discussion
There are several findings in this clinical study. First, the level of circulating CD133+CD34+ progenitors was lower in IS patients than that in normal controls. Second, the day 1 level of circulating CD133+CD34+ cells varied in different IS subgroups and inversely correlated with NIHSS and IMT, and patients with a higher level of CD133+CD34+ cells on day 7 had a better short-term outcome. Third, the increment rates of CD133+CD34+ cells and plasma SDF-1α were positively correlated within the week following admission. The increment rates of CD133+CD34+ cells could predict the short-term outcome of IS. The level of SDF-1α was negatively correlated with the NIHSS and infarct volume. These data well demonstrate the perspectives of using CD133+CD34+ cells and SDF-1α as biological predictors for IS.
Circulating progenitor cells have been shown to participate in tissue repair 19 and angiogenesis 20 in response to ischemic injury. Various combinations of surface antigens including CD34, CD133, KDR, VEGFR2, and CD62E have been used to define the phenotypes of circulating progenitors 3. CD133 marker is expressed relatively earlier on progenitor cells from human bone marrow, where KDR is expressed in the late phase of progenitors 21. A previous study has demonstrated that reduced circulating CD34+KDR+ cells could contribute to the progression of carotid atherosclerosis 22. Later, the level of circulating CD133+CD34+ cells was reported to be negatively associated with the level of neuroinflammatory factors in early IS patients 4. Although, there is no study directly showing the relationship between circulating CD133+CD34+ cells and IS. In this study, we found that the level of circulating CD133+CD34+ cells was significantly higher in IS patients than that in at-risk subjects, suggesting the mobilization of progenitor cells into systemic circulation in response to ischemic injury. This finding is in agreement with another study showing circulating endothelial progenitors were increased in acute IS 23. In addition, our data shows that there is a lower level of CD133+CD34+ cells in IS and at-risk groups when compared to that in normal subjects. This finding is well supported by our previous animal studies 18, 24 and other clinical trials 25, 26 showing a lower level of circulating endothelial progenitors in stroke risk conditions such as hypertension and diabetes.
Another interesting finding is that the level of circulating CD133+CD34+ cells varied among different IS subtypes. The LAA stroke patients had the lowest level of CD133+CD34+ cells. The CE and UE patients had the same level of CD133+CD34+ cells, but both of them were lower as compared to that in SAO group. This variation may depend on different pathogeneses among stroke subgroups. For example, the ultrasonography analysis revealed that LAA patients had the highest prevalence rates of unstable plaque, atherosclerosis and artery stenosis. We also found that the stroke patients with carotid plaques had a significantly lower level of CD133+CD34+ cells than those without carotid plaques. Additionally, we found that the circulating CD133+CD34+ cell level was inversely correlated with the carotid IMT value, which is a sign of atherosclerotic remodeling. These data indicate that the level of circulating CD133+CD34+ cells correlate with the severity of carotid artery injury.
In our study, the level of CD133+CD34+ progenitors inversely correlated with the NIHSS score, which indicated that reduction in circulating CD133+CD34+ cell level can predict the severity of neurological impairment in IS patients. Additionally, a high CD133+CD34+ progenitor level on day 7 and a higher increment rate of it in the first week were associated with a lower mRS at day 21, suggesting the predictive ability of the circulating CD133+CD34+ cells on IS outcome. These data together indicate that both the absolute level of circulating CD133+CD34+ cells and the increment rate of CD133+CD34+ cells are useful in predicting the neurological impairment and outcome of IS.
The SDF-1α /C-X-C chemokine receptor type 4(CXCR4) axis plays a critical role in progenitor cell mobilization, migration and homing for mediating angiogenesis and tissue repair 3, 27. The role of SDF-1α / CXCR4 axis in cerebral repair following IS has been previously revealed by others 27 and us 3, 28. In this clinical study, we analyzed the relationship between plasma SDF-1α level and infarct volume as well as NIHSS score by using the spearman's rank test. We found that there was a positive correlation between the increment rates of CD133+CD34+ cells and SDF-1α. This data is supported by another clinical study showing the relationship between plasma SDF-1α and the level of circulating progenitors determined by colony forming assay 29. More importantly, we found that plasma SDF-1α levels at day 1 and/or day 7 negatively correlated with NIHSS score and the acute infarct volume, suggesting its potential for predicting IS severity. Our findings are also in agreement with a previous study showing that SDF-1α is correlated with circulating CD133+KDR+, CD34+KDR+ and CD133+CD34+KDR+ progenitors 8.
In conclusion, the data of this study indicate that circulating CD133+CD34+ progenitor cells and plasma SDF-1α could be useful parameters for predicting the severity and prognosis of acute IS.
Acknowledgements
We thank Michelle Durrant in Boonshoft School of Medicine at Wright State University for reading the proof.
Sources of Funding
This work was supported by National Natural Science Foundation of China (NSFC, # 81271214, # 81270195), Guangdong Province Natural Science of Foundation (# S2011010004879), and National Heart, Lung, and Blood Institute (HL-098637, Y.C.).
Footnotes
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Disclosures
There is no conflict of interest.
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