Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Lin, Yunpeng; Luo, Lan; Sun, Jian; Gao, Weiwei; Tian, Ye; Park, Eugene; Baker, Andrew J.; Chen, Jieli; Jiang, Rongcai; Zhang, Jianning

doi:10.14336/ad.2016.0610

Cited by 10 publications

(9 citation statements)

References 38 publications

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“…Specifically, we found that these CXCR7-positive cells in the peri-infarcted regions are predominantly astrocytes in human. Consistently, previous studies have documented that, astrocytes show the rare expression of CXCR4 in the developing and injured brain, whereas throughout the brain a much larger subset of astrocytes seem to express CXCR7 [ 10 , 32 , 33 ]. The origin of the CXCR7-psotive astrocytes in the cortical penumbra is unknown.…”

Section: Discussionsupporting

confidence: 85%

SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 85%

SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke

et al. 2018

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“…Thereafter, DMEM containing LY294002 (50μM) and/or SDF-1 neutralizing antibody(10μg/ml) were separately injected into irradiated mice during the following 5 days. According to the FACS-captured CD31/CD34/CD133 triple-positive (TP) in peripheral blood, this was used for defining circulating EPCs (Figure 6D and Supplementary Figure 1 ), which was in line with previous studies [ 15 , 16 ]. Here, we found that when injected with DMEM containing SDF-1α antibody and/or LY294002, the numbers of circulating EPCs were significantly decreased compared to the MSC-CM group, suggesting that SDF-1α neutralization and PI3K inhibition hampered EPC recruitment (Figure 6D and 6E ).…”

Section: Resultssupporting

confidence: 70%

“…In addition, FACS analysis also confirmed that the amounts of both intra-villi CD31-single and CD31/CD105-DPcells in the IR+MSC-CM group were significantly higher than those in other groups (Figure 5B, 5C and 5D ), indicating microvascular restoration after MSC-CM treatment. Because of our test revealing that hAd-MSCs could secrete SDF-1α, a potent cytokine in recruiting EPCs to vascular injury [ 15 , 16 ], we then compared SDF-1α levels within irradiated intestine (Figure 5E ). As we found in the IR+DMEM group, SDF-1α levels were slightly increased in irradiated intestine compared to healthy controls.…”

Section: Resultsmentioning

confidence: 99%

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MSC-derived cytokines repair radiation-induced intra-villi microvascular injury

et al. 2017

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Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose-derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro. Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6 and TNF-α, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1α and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1α and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine.

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“…A previous report found that the level of SDF-1 protein in the serum of GC-treated patients was significantly decreased compared with untreated patients ( 63 ). Because the biologic effects of chemokines are mediated by their corresponding receptors, the interplay between SDF-1 and CXCR4 may provide another way to regulate the distribution of circulating EPCs ( 64 ). Similar to our previous finding that GCs reduced SDF-1 production in MSCs ( 5 ), the present study showed that GCs also reduced the CXCR4 expression in EPCs.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Impaired the Wound Healing Ability of Endothelial Progenitor Cells by Reducing the Expression of CXCR4 in the PGE2 Pathway

et al. 2018

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Background: Endothelial progenitor cells (EPCs) can be used to treat ischemic disease in cell-based therapy owing to their neovascularization potential. Glucocorticoids (GCs) have been widely used as strong anti-inflammatory reagents. However, despite their beneficial effects, side effects, such as impairing wound healing are commonly reported with GC-based therapy, and the effects of GC therapy on the wound healing function of EPCs are unclear.Methods: In this study, we investigated how GC treatment affects the characteristics and wound healing function of EPCs.Results: We found that GC treatment reduced the proliferative ability of EPCs. In addition, the expression of CXCR4 was dramatically impaired, which suppressed the migration of EPCs. A transplantation study in a flap mouse model revealed that GC-treated EPCs showed a poor homing ability to injured sites and a low activity for recruiting inflammatory cells, which led to wound healing dysfunction. Impairment of prostaglandin E2 (PGE2) synthases, cyclooxygenase (COX2) and microsomal PGE2 synthase 1 (mPEGS1) were identified as being involved in the GC-induced impairment of the CXCR4 expression in EPCs. Treatment with PGE2 rescued the expression of CXCR4 and restored the migration ability of GC-treated EPCs. In addition, the PGE2 signal that activated the PI3K/AKT pathway was identified to be involved in the regulation of CXCR4 in EPCs under the effects of GCs. In addition, similar negative effects of GCs were observed in EPCs under hypoxic conditions. Under hypoxic conditions, GCs independently impaired the PGE2 and HIF2α pathways, which downregulated the expression of CXCR4 in EPCs. Our findings highlighted the influences of GCs on the characteristics and functions of EPCs, suggesting that the use of EPCs for autologous cell transplantation in patients who have used GCs for a long time should be considered carefully.

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Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Cited by 10 publications

References 38 publications

SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke

SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke

MSC-derived cytokines repair radiation-induced intra-villi microvascular injury

Glucocorticoid Impaired the Wound Healing Ability of Endothelial Progenitor Cells by Reducing the Expression of CXCR4 in the PGE2 Pathway

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