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Background: Chemotherapy can induce premature ovarian insufficiency (POI). POI causes multiple sequelae and is currently incurable. Our previous studies have demonstrated that systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) can home to chemotherapy-induced POI ovaries, and thus reduce ovarian injury and improve ovarian function in rats with POI. However, the cellular mechanisms that direct the migration and homing of hAD-MSCs to chemotherapy-induced POI ovaries are barely understood. This study was to investigate the role of SDF-1/CXCR4 axis in the migration and homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries and its relevant downstream signaling pathways.Methods: CXCR4 expression in hAD-MSCs was tested by western blot and immunofluorescence assay. hAD-MSC migration was tested by transwell migration assay. SDF-1 level in rats was detected by ELISA. 72 of female SD rats were randomly divided into the control, POI, hAD-MSCs and hAD-MSCs+AMD3100 groups. POI rat models were established by intraperitoneal injection of cyclophosphamide. For the inhibitor treatment, hAD-MSCs were pretreated with AMD3100 before transplantation. hAD-MSCs labeled with PKH26 were injected into the tail vein of POI rats at 24 h after chemotherapy. After hAD-MSC transplantation, the homing of hAD-MSCs in ovaries, and ovarian function and pathological changes were examined. To further investigate molecular mechanisms, PI3K/Akt and ERK1/2 signaling pathways were detected. Results: hAD-MSCs expressed CXCR4. SDF-1 induced hAD-MSC migration in vitro. SDF-1 levels in ovaries and serum significantly increased in POI rats induced by chemotherapy, and POI ovaries attracted the homing of hAD-MSCs expressing CXCR4. The block of SDF-1/CXCR4 axis with AMD3100 can significantly reduce the number of hAD-MSCs homing to the POI ovaries, and further reduce their efficacy in POI treatment. The binding of SDF-1 to CXCR4 activated PI3K/Akt signaling pathway, and LY294002 significantly inhibited hAD-MSC migration induced by SDF-1 in vitro. Moreover, inhibition of PI3K/Akt signaling pathway significantly reduced the number of systemically transplanted hAD-MSCs homing to chemotherapy-induced POI ovaries in rats.Conclusions: SDF-1/CXCR4 axis partially mediates the migration and homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in rats, and PI3K/Akt signaling pathway might be involved in the migration and homing of hAD-MSCs mediated by SDF-1/CXCR4 axis.

In order to investigate the effect of TN14003 and its mechanism on cartilage degeneration in vitro and in vivo. P1 chondrocytes isolated from cartilage tissues of OA patients who underwent total knee arthroplasty were randomly assigned to blank control group, TN14003 group, T140 group, and AMD3100 group in vitro. Each group cells were cultured for 1, 2, 4, 6, 8, 10 days. Cell morphology were observed under inverted phase-contrast microscope and examined using MTT assay, flow cytometry, ELISA (MMPs in the chondrocyte medium) and quantitative real-time PCR (mRNA expressions of Col II and ACAN). Moreover, 96 male Hartley guinea pigs with spontaneous OA were randomly assigned to examine the effect of TN14003, T140, and AMD3100 in vivo. After 12 weeks, guinea pigs were sacrificed, the knee articular cartilage histopathology was analyzed. No difference in morphology, proliferation rate and apoptosis among four groups (P > 0.05). The content of MMP-3 and MMP-13, mRNA expression levels of ACAN and Col II were significantly lower in TN14003 group compared with other groups (P in vivo. TN14003 could effective targeted to prevention and treatment of OA.

Aim: The aim of the present study was to investigate the effect of the mobilization of EPCs by AMD3100 combined with G-CSF on wound healing in diabetic mice. Methods: The full-thickness excisional wounds model of diabetic mice (db/db) was examined by hematoxylin and eosin staining, immunohistochemical staining, and western blotting to compare the wound healing and neovascularization among the combination, AMD3100 alone, G-CSF alone, and control groups. Results: The wounds reached the complete closure in the combination, AMD3100 alone, G-CSF alone, and control groups on days 17, 20, 21, 21 after surgery, respectively. In addition, the combination group promoted the inflammatory cell recruitment and glandular formation. On day 10 from injury, the protein expression of CD31 in the combination group was significantly higher compared with the other three groups ( p Conclusion: The mobilization of endogenous EPCs by AMD3100 combine with G-CSF is able to enhance the complete healing of full-thickness wounds and neovascularization in db/db mice may by SDF-1/CXCR4 axis. These findings provided a novel method and indication of duration of mobilization on diabetic wound healing and tissue regeneration.

Background: Platinum-based treatment of locally advanced non-small cell lung cancer (NSCLC) provides some clinical benefit in controlling local disease but is ineffective on metastatic dissemination. Rising evidence suggests that chemotherapy can promote an inflammatory reaction supportive of metastasis growth.We previously demonstrated that cisplatin treatment of mouse xenografts enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development. We hypothesize here that the SDF-1/CXCR4 axis, implied in MICs migration and in stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects. Results: To study the effects of cisplatin in promoting a pre-metastatic niche, tumor-free naïve SCID mice were treated with cisplatin plus/minus peptide R, a novel inhibitor of CXCR4. Cisplatin resulted in a rapid expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) in the bone marrow, concomitantly with their recruitment to murine lungs guided by enhanced endothelial release of SFD-1. Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases enriched in CD133+CXCR4+ MICs. We proposed that the abundance of CXCR4+IM together with increased endothelial permeability caused by cisplatin favors tumor cells extravasations and the expansion of MICs through SDF-1/CXCR4 axis activation. Combination treatment with a CXCR4 inhibitor prevented IM recruitment, MICs expansion and consequently abolished metastasis overgrowth induced by cisplatin. Combination treatment of H460 subcutaneous xenografts in a regimen mimicking clinical setting revealed that cisplatin also caused tumor release of SDF-1 able to trigger local expansion of MICs subset and to recruit CXCR4+tumor associated macrophages involved in tumor cells intravasation. Stromal SDF-1 induced by cisplatin at distant site also co-recruited MICs and CCR2+CXCR4+IM, promoting spontaneous metastasis formation that can be counteracted by CXCR4 blockade. We confirmed in clinical setting that platinum-based neoadjuvant treatment of NSCLC patients significantly increases tumor SDF-1 expression. Moreover, an higher expression of tumor SDF-1 after cisplatin neo-adjuvant treatment was associated with patients' shorter DFS (p=0,0056; Hazards Ratio= 3,1) and poor OS (p=0,029; Hazards Ratio= 3,46). Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective results for lung cancer treatment Citation Format: Giulia Bertolini, Valeria Cancila, Orazio Fortunato, Giuseppe Lo Russo, Monica Tortoreto, Giovanni Centonze, Massimo Milione, Claudio Tripodo, Stefania Scala, Gabriella Sozzi, Luca Roz. Cisplatin-induced activation of SDF-1/CXCR4 axis sustains lung cancer metastasis by promoting co-recruitment of metastasis initiating cells and inflammatory monocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1106.

The study was to evaluate whether fibrotic markers, endometrial receptivity markers and SDF-1/CXCR4 had been changed in the treatment of intrauterine adhesions (IUAs) by different dosages of estrogen.A total of 39 patients with IUAs were treated with EV 4 mg or 9 mg randomly post-surgery. TGF-β1/MMP-9, VEGF/αvβ3 and SDF-1/CXCR4 were detected in endometrial tissue before and after treatment by real-time PCR and Western blot.TGF-β1 and MMP-9 expression significantly decreased after treatment for 3 months than before (p .05), the falling range was larger with EV 4 mg than 9 mg in the mild-moderate degree IUAs (p .05); Integrin avβ3 expression significantly increased after treatment for 3 months than before (p .05), the variation range was larger with EV 4 mg than 9 mg (p .05); CXCR4 expression had no significant change after treatment 3 months compared to that before treatment (p .05). SDF-1 presented an upward tendency at early phase, and it came back to the level of pre-surgery. But there were no significant difference between treatment with 4 mg and 9 mg in the rate of menstrual restoration and pregnancy follow-up 3 months after the treatment.Endometrium fibrosis may be inhibited and endometrium receptivity may be improved by estrogen with moderate dosage therapy. Compared to the large one, it seems to be advantageous.

Salvia Miltiorrhizae Bge, a popular Chinese herb has been widely adopted for use in Chinese hospitals for both the prevention and the active management of cardiovascular disease. there is no study on its cardioprotective effects against HF and more importantly, the underlying mechanisms of its beneficial effects by SDF-1/CXCR4 axis remain poorly understood. This study was performed to investigate the protective effects and possible mechanism of aqueous extract of Salvia miltiorrhiza (AESM) on HF rats. In the study, cardioprotective effects of AESM on HF rats was evaluated by herat function, myocardial pathology, myocardial cell proliferation, SDF-1, CXCR4 and Bcl-2 family mRNA expressions. In the experiment, we found that AESM exerted beneficially protective effects on the HF rats, mainly recoverying normal heart function, myocardial pathology and myocardial cell proliferation. The underlying mechanism of these protective effects of AESM appeared to involve improving the SDF-1/CXCR4 axis and Bcl-2 family expressions.

// Guo-Dong Wang 1, * , Yi-Xun Liu 1, * , Xiao Wang 1 , Yong-Le Zhang 1 , Ya-Dong Zhang 2 , Feng Xue 2 1 Department of Orthopedic, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China 2 Department of Orthopedic, Shanghai Fengxian Central Hospital, Branch of the Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 201400, P.R. China * These are co-first authors Correspondence to: Xiao Wang, email: drwx111@163.com Keywords: bone marrow-derived mesenchymal stem cells, stromal cell-derived factor-l, chemotaxis cytokine receptor-4, spinal cord injury, hind limb motor function Received: June 29, 2016 Accepted: December 16, 2016 Published: January 13, 2017 ABSTRACT This study aims to explore the role of the SDF-1/CXCR4 axis in mediating BMSCs and SCI recovery. BMSCs were collected and SCI rat models were established. Wistar rats were assigned into the blank control, sham, SCI, SCI + BMSCs, SCI + BMSCs + SDF-1, SCI + BMSCs + AMD3100 (an inhibitor of SDF-1/CXCR4 axis) and SCI + BMSCs + SDF-1 + AMD3100 groups. Hind limb motor function was measured 7, 14, 21 and 28 days after operation. qRT-PCR, western blotting and ELISA was performed to determine the expressions of SDF-1, CXCR4, NGF, BDNF, GFAP and GAP-43, TNF-α, IL-1β, L-6 and IFN-γ. Hind limb motor function scores 7 days after the operation were reduced in the SCI rats of the blank control and sham groups. Hind limb function was found to be better in the SCI + BMSCs and SCI + BMSCs + SDF-1 groups than in the SCI, SCI + BMSCs + AMD3100 and SCI + BMSCs + SDF-1 + AMD3100 groups 14, 21 and 28 days after operation. Furthermore, the SCI group had lower SDF-1, CXCR4, NGF, BDNF and GAP-43 expressions but higher GFAP, TNF-α, IL-1β, IL-6 and IFN-γ than the blank control and sham groups 28 days after operation. While, the SCI + BMSCs, SCI + BMSCs + SDF-1 and SCI + BMSCs + SDF-1 + AMD3100 groups displayed opposite trends to the SCI and SCI + BMSCs + AMD3100 groups. In conclusion, SDF-1/CXCR4 axis promotes recovery after SCI by mediating BMSCs.

The interaction between stromal cell-derived factor 1 (SDF-1) and its receptor chemokine CXC motif receptor 4 (CXCR4) plays a vital role in the engraftment of mesenchymal stem cells (MSCs) in the injured myocardium. Our previous studies have demonstrated that atorvastatin (ATV) could improve the

Fibroproliferative disorders are an ongoing clinical issue that is prevalent within society today. These disorders generally manifest themselves by an overproduction of fibrotic tissue with unknown provocation resulting in numerous detrimental defects. Cellular migration of blood-borne cells via the chemotactic pathway, consisting of stromal cell-derived factor 1 and its receptor, CXCR4, has been strongly implicated in post-burn hypertrophic scar formation. Evidence has shown this pathway has potential as a therapeutic target in the formation of hypertrophic scar and likely in other fibroproliferative disorders.

The stromal-cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) chemokine axis plays a key role in tumor migration. Here, we analyzed the axis in uveal melanoma (UM) proliferation and migration and investigated the effect of a chemical inhibitor of CXCR4, AMD3100, on UM. We found that CXCR4 was expressed in all five UM cell lines tested as well as the retinal pigment epithelium cell line ARPE-19 cells, while CXCR7 was only detected in OM290 and VUP cell lines. SDF-1 promotes the proliferation and migration of OCM-1 and OCM431 cell lines, while AMD3100 weakens this function. Taken together, our results show that the SDF-1/CXCR4 chemokine axis plays a key role in UM cell proliferation and migration and that AMD3100 can alleviate this function, which may offer a hint for UM treatment.

MSCs have become a popular target for developing end-stage liver therapies. In this study, two models of bone marrow chimeric mice were used to construct the liver failure models. Then it was found that MSCs can transdifferentiate into hepatocyte-like cells and these hepatocyte-like cells can significantly express albumin. Furthermore it was also found that MSCs can fuse with the hepatocytes and these cells had the proliferation activity. However, the percentage of transdifferentiation was significantly higher than fusion. So it was considered that MSCs which transdifferentiated into hepatocyte-likes cells played important roles for repairing the injuring liver function.

Astragaloside IV (AsIV) is the major effective component extracted from the Chinese herb Astragalus membranaceus, which has been widely used to treat cardiovascular disease. Recent studies have shown that AsIV can potentially protect the arteries from atherosclerosis, but the mechanisms of action

Pathological angiogenesis, which occurs during chronic inflammation or tumor growth, results when positive and negative angiogenic regulators are disrupted. The chemokine stromal-cell derived facto...

Stromal cell-derived factor-1 (SDF-1) causes chemotaxis of CXCR4-expressing bone marrow-derived cells. SDF-1 is involved in the pathogenesis of various vascular diseases, including those of the eye. However, the role of SDF-1 in neuronal diseases is not completely understood. Here, we show higher SDF-1 levels in the vitreous humor of patients with retinal detachment (RD) compared with normal patients. SDF-1 correlated positively with the duration as well as the extent of RD. Furthermore, SDF-1 correlated significantly with levels of interleukin-6 and interleukin-8, but not with vascular endothelial growth factor. Western blot analysis results showed significant SDF-1 up-regulation in detached rat retinas compared with normal animals. Immunohistochemistry data showed that SDF-1 was co-localized with the glial cells of the detached retina. SDF-1 blockade with a neutralizing antibody increased photoreceptor cell loss and macrophage accumulation in the subretinal space. The retinal precursor cell line R28 expressed CXCR4. SDF-1 rescued serum starvation-induced apoptosis in R28 cells and enhanced their ability to participate in wound closure in a scratch assay. Our results indicate a surprising, protective role for SDF-1 in RD. This effect may be mediated directly or indirectly through other cell types.

OBJECTIVE To study the expression of HIF-1alpha and SDF-1/CXCR4 in repopulating H22 tumor tissue and the mechanism of angiogenesis of polypeptide extract from scorpion venom (PESV) during chemotherapy treatment. METHOD The expression of HIF-1alpha and SDF-1/CXCR4 in H22 tumor tissue was monitored by immunohistochemistry, and the expression level was determined by Qwin V3 image analyzing software. The correlation between HIF-1alpha and SDF-1 was analyzed. SDF-1 content was detected by ELISA. RESULT HIF-1alpha expression was found no difference in model group between 14 d and 21 d, and up-regulated in 28 d. There was no change of HIF-1alpha expression was observed in low-dose PESV group. In high-dose PESV group, the level of HIF-1alpha expression was high in 14 d and low in 21 d. ELISA detecting showed SDF-1 content increased slowly from 14 d to 21 d, highly from 21 d to 28 d. But in high-dose PESV groups, the content increased slowly all the time. The immunohitochemistry method got the same result with ELISA. Correlation analysis showed r = 0.805. CXCR4 expression down-regulated in two PESV treated groups, and no difference was found between these two groups. CONCLUSION HIF-1alpha and SDF-1 participated in VEGF expression and angiogenesis in tumor tissue during chemotherapy, while PESV could inhibit the expression of HIF-1alpha and SDF-I.

We have previously demonstrated that stromal cell-derived factor (SDF)-1/CXCR4 system is involved in the metastatic process of oral cancer. Recently, small non coding RNAs, microRNAs (miRNAs) are involved in the metastatic process of several types of cancers. However, the miRNAs contributed to metastases induced by the SDF-1/CXCR4 system in oral cancer are largely unknown. Thus, we examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system, using oral cancer cells, B88-SDF-1, which exhibits functional CXCR4 and distant metastatic potential, in vivo. We examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system by use of a miRNA microarray representing approximately 1700 miRNA. Consequnetly, we identified 4 kinds of upregulated-miRNAs in B88-SDF-1 cells whose functions are unknown. Among these miRNAs, we confirmed the upregulation of miR-5XX in B88-SDF-1 cells by the real-time PCR analysis. Although LNA-based miR-5XX inhibitor did not affect the growth of the cells, it did significantly inhibit the migration of B88-SDF-1 cells. Thus, we examined the target gene(s) of miR-5XX in the SDF-1/CXCR4 system. cDNA microarray analysis revealed that 6 kinds of mRNA containing the predictive binding site of miR-5XX were upregulated by the treatment with miR-5XX inhibitor. Furthermore, gene A mRNA and protein was downregulated in B88-SDF-1 cells, and upregulated by the treatment with miR-5XX inhibitor. These results indicating that SDF-1/CXCR4 system might regulate the metastases of oral cancer by the downregulation of gene A via upregulation of miR-5XX. Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Tetsuya Tamatani, Hirokazu Nagai, Youji Miyamoto. Functional analysis of metastasis-related microRNA induced by the stromal-cell derived factor (SDF)-1/CXCR4 system in oral cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2013-2697

CorrectionAfter publication of our recent article [1], we noticed that this study was initiated in Qian Chens lab and that we had inadvertently omitted Qian Chen as a co-author. e study was also supported by other grants from NIH. Revised acknowledgment and authors contribution para-graphs appear below. e author list is now complete and the competing interests section modi“ ed accordingly.

Previously, we identified a metastasis-candidate gene, metabotropic glutamate receptor (mGluR)-5 by using an oral cancer cell line, B88-SDF-1, which have an autocrine stromal cell-derived factor (SDF)-1/CXCR4 system and distant metastatic potentials in vivo. In this study, we examined the effect of mGluR5 antagonists on the SDF-1/CXCR4 dependent-metastases in oral cancer. We used 2 kinds of mGluR5-specific antagonists, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). These antagonists did not affect the growth of B88-SDF-1 cells, but did inhibit the enhanced-migration of the cells. Under these conditions, actin polymerization and pseudopodia formation were also inhibited by the treatment with MPEP and MTEP. In order to confirm the drug toxicities, these antagonists were intraperitoneally injected into wild-type mice for 4 weeks. All the mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not show side effects, such as hematotoxicity, allergic reaction and body weight loss. When the B88-SDF-1 cells were transplanted into the vein of nude mice, these antagonists significantly inhibited the lung metastases of the cells. These results suggested that blockade of mGluR5, using antagonists such as MPEP and MTEP, may be effective at preventing metastasis in patients with CXCR4-related oral cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2011-2440