Elevated levels of plasma inactive stromal cell derived factor-1α predict poor long-term outcomes in diabetic patients following percutaneous coronary intervention.

BACKGROUND: Since the complication of diabetes mellitus (DM) is a risk for adverse cardiovascular outcomes in patients with coronary artery disease (CAD), appropriate risk estimation is needed in diabetic patients following percutaneous coronary intervention (PCI). However, there is no useful biomarker to predict outcomes in this population. Although stromal cell derived factor-1α (SDF-1α), a circulating chemokine, was shown to have cardioprotective roles, the prognostic impact of SDF-1α in diabetic patients with CAD is yet to be fully elucidated. Moreover, roles of SDF-1α isoforms in outcome prediction remain unclear. Therefore, this study aimed to assess the prognostic implication of three forms of SDF-1α including total, active, and inactive forms of SDF-1α in patients with DM and after PCI. METHODS: This single-center retrospective analysis involved consecutive patients with diabetes who underwent PCI for the first time between 2008 and 2018 (n = 849). Primary and secondary outcome measures were all-cause death and the composite of cardiovascular death, non-fatal myocardial infarction, and ischemic stroke (3P-MACE), respectively. For determining plasma levels of SDF-1α, we measured not only total, but also the active type of SDF-1α by ELISA. Inactive isoform of the SDF-1α was calculated by subtracting the active isoform from total SDF-1α. RESULTS: Unadjusted Kaplan-Meier analyses revealed increased risk of both all-cause death and 3P-MACE in patients with elevated levels of inactive SDF-1α. However, plasma levels of total and active SDF-1α were not associated with cumulative incidences of outcome measures. Multivariate Cox hazard analyses repeatedly indicated the 1 higher log-transformed inactive SDF-1α was significantly associated with increased risk of all-cause death (hazard ratio (HR): 2.64, 95% confidence interval (CI): 1.28-5.34, p = 0.008) and 3P-MACE (HR: 2.51, 95% CI: 1.12-5.46, p = 0.02). Moreover, the predictive performance of inactive SDF-1α was higher than that of total SDF-1α (C-statistics of inactive and total SDF-1α for all-cause death: 0.631 vs 0.554, for 3P-MACE: 0.623 vs 0.524, respectively). CONCLUSION: The study results indicate that elevated levels of plasma inactive SDF-1α might be a useful indicator of poor long-term outcomes in diabetic patients following PCI. TRIAL REGISTRATION: This study describes a retrospective analysis of a prospective registry database of patients who underwent PCI at Juntendo University Hospital, Tokyo, Japan (Juntendo Physicians' Alliance for Clinical Trials, J-PACT), which is publicly registered (University Medical Information Network Japan-Clinical Trials Registry, UMIN-CTR 000035587).

CXCR4-modified CAR-T cells suppresses MDSCs recruitment via STAT3/NF-κB/SDF-1α axis to enhance efficacy against pancreatic cancer.

Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer-associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then, we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy in vivo. Mechanistically, the activation of signal transducer and activator of transcription 3 (STAT3) signaling was impaired in CXCR4 CAR-T cells, which reduced the release of inflammatory factors, such as tumor necrosis factor-α, IL-6, and IL-17A. Then, the lower release of inflammatory factors suppressed SDF-1α secretion in CAFs via the nuclear factor κB (NF-κB) pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and also suppress MDSC migration via the STAT3/NF-κB/SDF-1α axis to obtain better efficacy in treating CLDN18.2-positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.

SDF-1/CXCR4 axis participants in the pathophysiology of adult patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is characterized by an abundance of moyamoya vessels; however, the precise mechanism driving the spontaneous angiogenesis of these compensatory vessels remains unclear. Previous research has established a link between the stromal cell-derived factor-1 (SDF-1)/ CXC receptor 4 (CXCR4) axis and angiogenesis under hypoxic conditions. Nevertheless, the alterations in this axis within the cerebrospinal fluid, arachnoid membranes and vascular tissue of MMD patients have not been fully investigated. METHODS: Our study enrolled 66 adult MMD patients and 61 patients with atherosclerotic vascular disease (ACVD). We investigated the SDF-1 concentration in cerebrospinal fluid (CSF) and CXCR4 expression level on the arachnoid membranes and vascular tissue. We utilized enzyme-linked immunosorbent assay and immunohistochemistr. Additionally, we cultured and stimulated human brain microvascular endothelial cells (HBMECs) and smooth muscle cells (SMCs) under oxygen and glucose deprivation (OGD) conditions followed by reoxygenation, to examine any changes in the SDF-1/CXCR4 axis. RESULTS: The results demonstrated an elevation in the level of SDF-1 in CSF among MMD patients compared to those with ACVD. Moreover, the expression of CXCR4 in arachnoid membranes and vascular tissue showed a similar trend. Furthermore, the content of CXCR4 in HBMECs and SMCs increased with the duration of ischemia and hypoxia. However, it was observed that the expression of CXCR4 decreased at OGD/R 24h compared to OGD 24h. The temporal pattern of SDF-1 expression in HBMECs and SMCs mirrored that of CXCR4 expression. CONCLUSION: These findings indicate a critical role for the SDF-1/CXCR4 axis in the angiogenesis of moyamoya disease.

[Stromal Cell-Derived Factor 1α Inhibits Chondrocyte Apoptosis and Promotes Autophagy Through the Akt Signaling Pathway]. / åŸºè´¨ç»†èƒžè¡ç”Ÿå› å­1α通过Akt信号通路抑制软骨细胞凋亡并促进自噬.

Objective: To investigate the effects of stromal cell-derived factor 1α (SDF-1α) on the apoptosis and autophagy of chondrocytes and the underlying mechanisms. Methods: Chondrocytes were isolated from the knee joints of neonatal mice. The chondrocytes were then stimulated with 0 (the control group), 50, 100, and 200 ng/mL of SDF-1α. CCK-8 assay was performed to determine the effects of SDF-1α stimulation for 24 h, 48 h, and 72 h on the viability of the chondrocytes. Wound healing assay was conducted to determine the effects of SDF-1α stimulation for 12 h and 24 h on chondrocyte migration. The changes in the expression of Akt signaling pathway proteins in chondrocytes were determined by Western blot assay. Chondrocytes were stimulated with 0 (the control group) and 200 ng/mL of SDF-1α. Flow cytometry was performed to determine the effect of SDF-1α on the apoptosis of chondrocytes. Transmission electron microscope was used to examine the effect of SDF-1α on chondrocyte autophagy. Immunofluorescence staining assays were performed to visualize the differences in p-Akt expression and distribution in chondrocytes treated with SDF-1α. Results: Compared with the control group, findings for the experimental groups showed that SDF-1α at the concentrations of 50, 100, and 200 ng/mL did not decrease chondrocyte activity at any time point (P<0.01) and it consistently promoted chondrocyte migration at 24 h (P<0.05). Western blot results revealed that, in comparison to the control group, SDF-1α at concentrations of 50, 100, and 200 ng/mL significantly up-regulated the protein expression of p-Akt in chondrocytes, while no significant difference in Akt expression was observed. Flow cytometry demonstrated that SDF-1α could inhibit chondrocyte apoptosis (P<0.05) and transmission electron microscopic observation showed that SDF-1α promoted chondrocyte autophagy (P<0.05). Immunofluorescence staining showed that the expression of p-Akt in chondrocytes was concentrated in the perinuclear area of the cells and this expression was further enhanced in the perinuclear area of the chondrocytes after treatment with SDF-1α. Conclusion: SDF-1α inhibits chondrocyte apoptosis and promotes chondrocyte migration and autophagy through activating the Akt signaling pathway.

Prognostic significance of plasma SDF-1 in acute ischemic stroke patients with diabetes mellitus: the CATIS trial.

BACKGROUND AND OBJECTIVES: Evidence on the associations between baseline stromal cell-derived factor (SDF)-1 and clinical outcomes in acute ischemic stroke patients is lacking. The present study aimed to examine the relationship between plasma SDF-1 levels and clinical outcomes based on a large multicenter study of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). METHODS: Secondary analysis was conducted among 3,255 participants from the CATIS trial with a baseline measurement of plasma SDF-1 levels. We evaluated the associations between plasma SDF-1 levels and one-year recurrent stroke, cardiovascular events, and all-cause mortality using Cox regression models. We further investigated the prognostic effect of SDF-1 on clinical outcomes in patients with different characteristics. RESULTS: Higher plasma SDF-1 levels were not associated with recurrent stroke, cardiovascular events, and all-cause mortality at one-year after ischemic stroke (all P trend ≥ 0.05). There were significant interactions between plasma SDF-1 levels and history of diabetes mellitus on recurrent stroke (P = 0.005), cardiovascular events (P = 0.007) and all-cause mortality (P = 0.04) at one year. In patients with diabetes mellitus, plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events after adjustment for confounders. For example, 1-SD higher log-SDF-1 was associated with a hazard ratio (95% confidence interval) of 1.65 (1.18-2.32) for recurrent stroke and 1.47 (1.08-1.99) for the cardiovascular events, but not all-cause mortality 1.36 (0.96-1.93) at one year. However, there were no associations between plasma SDF-1 and clinical outcomes in patients without diabetes mellitus (all P > 0.05). The addition of plasma SDF-1 to the conventional risk factors model significantly improved the risk prediction of all outcomes. Similarly, findings between elevated SDF-1 levels and two-year outcomes were found only in patients with diabetes mellitus. CONCLUSIONS: Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus.

Biodegradable nano black phosphorus based SDF1-α delivery system ameliorates Erectile Dysfunction in a cavernous nerve injury rat model by recruiting endogenous stem/progenitor cells.

Stem cell (SC) therapy has been shown high prospects in erectile dysfunction (ED) treatment. Without ethical issues and risks of immune rejection and tumorigenesis of exogenous SC therapy, endogenous stem/progenitor cells (S/PCs) have a better potential for ED management, and their homing and redistribution are controlled by SDF1-α/CXCR4 axis. Considering black phosphorus nanosheet (BPNS) has emerged as an efficient and safe drug vehicle due to its large surface area, biodegradability, and the ability to retain and slowly release its loaded drugs, BPNS is utilized to load SDF1-α, a chemokine for S/PCs, to construct the BP@SDF1-α complex to efficiently recruit stem cells (SCs) by injury-site injection and thus ameliorate ED within the bilateral cavernous nerve injury (BCNI) rat models. We find that BP@SDF1-α can efficiently recruit exogenous SCs and endogenous S/PCs to corpus cavernosum and main pelvic ganglion (MPG) by local administration. Of note, ascribing to endogenous S/PCs recruitment, it also successfully alleviates ED in BCNI rat models by enhancing the protein expression levels of α-SMA, CD31, and nNOs, and eliciting less collagen deposition in the penis after its combined injection at corpus cavernosum and MPG. Thus, this study provides a new insight into the treatment of ED with endogenous S/PCs. BIODEGRADABLE NANO BLACK PHOSPHORUS BASED SDF1-α DELIVERY SYSTEM AMELIORATES ERECTILE DYSFUNCTION IN A CAVERNOUS NERVE INJURY RAT MODEL BY RECRUITING ENDOGENOUS STEM/PROGENITOR CELLS.

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: Subchondral bone sclerosis is a major feature of osteoarthritis (OA), and bone marrow mesenchymal stem cells (BMSCs) are presumed to play an important role in subchondral bone sclerosis. Accumulating evidence has shown that stromal cell-derived factor-1α (SDF-1α) plays a key role in bone metabolism-related diseases, but its role in OA pathogenesis remains largely unknown. The purpose of this study was to explore the role of SDF-1α expressed on BMSCs in subchondral bone sclerosis in an OA model. METHODS: In the present study, C57BL/6J mice were divided into the following three groups: the sham control, destabilization of the medial meniscus (DMM), and AMD3100-treated DMM (DMM + AMD3100) groups. The mice were sacrificed after 2 or 8 weeks, and samples were collected for histological and immunohistochemical analyses. OA severity was assessed by performing hematoxylin and eosin (HE) and safranin O-fast green staining. SDF-1α expression in the OA model was measured using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (q-PCR), and immunohistochemistry. Micro-CT was used to observe changes in subchondral bone in the OA model. CD44, CD90, RUNX2, and OCN expression in subchondral bone were measured using q-PCR and immunohistochemistry. In vitro, BMSCs were transfected with a recombinant lentivirus expressing SDF-1α, an empty vector (EV), or siRNA-SDF-1α. Western blot analysis, q-PCR, and immunofluorescence staining were used to confirm the successful transfection of BMSCs. The effect of SDF-1α on BMSC proliferation was evaluated by performing a CCK-8 assay and cell cycle analysis. The effect of SDF-1α on the osteogenic differentiation of BMSCs was assessed by performing alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Cyclin D1, RUNX2 and OCN expression were measured using Western blot analysis, q-PCR, and immunofluorescence staining. RESULTS: SDF-1α expression in the DMM-induced OA model increased. In the DMM + AMD3100 group, subchondral bone sclerosis was alleviated, OA was effectively relieved, and CD44, CD90, RUNX2, and OCN expression in subchondral bone was decreased. In vitro, high levels of SDF-1α promoted BMSC proliferation and increased osteogenic differentiation. Cyclin D1, RUNX2, and OCN expression increased. CONCLUSION: The results of this study reveal a new molecular mechanism underlying the pathogenesis of OA. The targeted regulation of SDF-1α may be clinically effective in suppressing OA progression.

Decreased Serum Stromal Cell-Derived Factor-1 in Patients with Familial Hypercholesterolemia and Its Strong Correlation with Lipoprotein Subfractions.

Stromal cell-derived factor-1 (SDF-1) is a chemokine that exerts multifaceted roles in atherosclerosis. However, its association with hyperlipidemia is contradictory. To date, serum SDF-1 and its correlations with lipid fractions and subfractions in heterozygous familial hypercholesterolemia (HeFH) have not been investigated. Eighty-one untreated patients with HeFH and 32 healthy control subjects were enrolled in the study. Serum SDF-1, oxidized LDL (oxLDL) and myeloperoxidase (MPO) were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly lower serum SDF-1 was found in HeFH patients compared to healthy controls. Significant negative correlations were detected between serum total cholesterol, triglycerides, LDL-cholesterol (LDL-C), apolipoprotein B100 (ApoB100) and SDF-1. Furthermore, serum SDF-1 negatively correlated with VLDL and IDL, as well as large LDL and large and intermediate HDL subfractions, while there was a positive correlation between mean LDL-size, small HDL and SDF-1. SDF-1 negatively correlated with oxLDL and MPO. A backward stepwise multiple regression analysis showed that the best predictors of serum SDF-1 were VLDL and oxLDL. The strong correlation of SDF-1 with lipid fractions and subfractions highlights the potential common pathways of SDF-1 and lipoprotein metabolism, which supports the role of SDF-1 in atherogenesis.

[Relationship between promoting effect of Zuogui Pills on angiogenesis of reproductive organs and mobilization factors GM-CSF, SDF-1, and their receptors of EPCs in early-aging rats].

This study aimed to investigate the relationship between the promoting effect of Zuogui Pills on ovarian and vaginal angiogenesis in early-aging rats and mobilization factors granulocyte-macrophage colony-stimulating factor(GM-CSF), stromal cell-derived factor-1(SDF-1), and their receptors of endothelial progenitor cells(EPCs) and explore the mechanism of Zuogui Pills in improving reproductive hypofunction in early-aging rats. Ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) was used to analyze the chemical components of the extract of Zuogui Pills. Forty 14-month-old female early-aging rats with estrous cycle disorder were randomly divided into a blank group, a conjugated estrogen group(conjugated estrogen suspension, 65 µg·kg~(-1)), and low-(11 g·kg~(-1)) and high-dose(33 g·kg~(-1)) Zuogui Pills groups, with 10 rats in each group. In addition, 10 4-month-old female rats were assigned to the youth control group. The rats in the blank group and the youth control group were treated with 20 g·kg~(-1) distilled water by gavage, while those in the groups with drug intervention were treated with corresponding drugs by gavage, once a day for 15 days. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of SDF-1 and GM-CSF in the mobilization of EPCs in serum. Hematoxylin-eosin(HE) staining was used to observe the changes in the number of ovarian follicles at all levels and corpus luteum, the number of vaginal epithelial layers, the number of vaginal folds, and the blood vessels of ovarian and vaginal tissues in the groups with drug intervention. Western blot was used to detect the expression of ER, GM-CSFR, CXCR4, and CXCR7 proteins in ovarian and vaginal tissues. As revealed by the results, the blank group showed decreased number of corpus luteum, gro-wing follicles at all levels, and blood vessels(P<0.05), decreased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal folds, and the number of vessels in the lamina propria(P<0.05), reduced content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and down-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). The groups with drug intervention showed increased number of growing follicles at all levels, corpus luteum, and blood vessels(P<0.05), decreased number of atresia follicles(P<0.05), increased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal mucosal folds, and the number of blood vessels in the lamina propria(P<0.05), increased content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and up-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). This experiment suggests that Zuogui Pills may promote ovarian and vaginal angiogenesis and improve the reproductive function of early-aging rats by up-regulating the levels of mobilization factors SDF-1, GM-CSF, and their receptors of EPCs.

Stromal cell-derived factor-1 exerts opposing roles through CXCR4 and CXCR7 in angiotensin II-induced adventitial remodeling.

Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling.

Coadministration of Curcumin and Hydromorphone Hydrochloride Alleviates Postoperative Pain in Rats.

This study aimed to explore the effect of curcumin and hydromorphone hydrochloride (HH) cotreatment on postoperative pain in rats. An incision + formaldehyde-induced pain rat model was established. Rats were treated with vehicle, curcumin, HH, or curcumin + HH. Paw mechanical withdrawal threshold and thermal withdrawal latency were measured at 1 d before surgery as well as 1 , 2 h, 1 , 3 , and 7 d after surgery to assess pain sensitivity. The L4-6 region of the spinal cord was collected from each rat at 2 h, 1 , 3 , and 7 d after surgery. Western blot analysis and immunohistochemical staining were carried out to detect the protein expression of pain-related genes. Quantitative real-time PCR and enzyme-linked immunosorbent assay were conducted to measure the expression and production of proinflammatory mediators. Compared with other groups, Curcumin + HH significantly reduced pain sensitivity in the model rats. Mechanistically, curcumin + HH suppressed protein expression of stromal cell-derived factor-1 (SDF-1), CXC chemokine receptor 4 (CXCR4), p-Akt, and c-fos while enhancing protein expression of nerve growth factor (NGF) in the dorsal root ganglia (DRG) of model rats. Curcumin + HH inhibited the expression and production of interleukin 1ß (IL-1ß), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and p65 nuclear factor kappa B (NF-κB) in the DRG. Coadministration of curcumin and HH alleviates incision + formaldehyde-induced pain in rats, possibly by suppressing the SDF-1/CXCR4 pathway and the production of proinflammatory mediators. Our results provide curcumin and HH cotreatment as a promising therapeutic strategy in the management of postoperative pain.

The SDF1-CXCR4 Axis Is Involved in the Hyperbaric Oxygen Therapy-Mediated Neuronal Cells Migration in Transient Brain Ischemic Rats.

Neurogenesis is a physiological response after cerebral ischemic injury to possibly repair the damaged neural network. Therefore, promoting neurogenesis is very important for functional recovery after cerebral ischemic injury. Our previous research indicated that hyperbaric oxygen therapy (HBOT) exerted neuroprotective effects, such as reducing cerebral infarction volume. The purposes of this study were to further explore the effects of HBOT on the neurogenesis and the expressions of cell migration factors, including the stromal cell-derived factor 1 (SDF1) and its target receptor, the CXC chemokine receptor 4 (CXCR4). Thirty-two Sprague-Dawley rats were divided into the control or HBO group after receiving transient middle cerebral artery occlusion (MCAO). HBOT began to intervene 24 h after MCAO under the pressure of 3 atmospheres for one hour per day for 21 days. Rats in the control group were placed in the same acrylic box without HBOT during the experiment. After the final intervention, half of the rats in each group were cardio-perfused with ice-cold saline followed by 4% paraformaldehyde under anesthesia. The brains were removed, dehydrated and cut into serial 20µm coronal sections for immunofluorescence staining to detect the markers of newborn cell (BrdU+), mature neuron cell (NeuN+), SDF1, and CXCR4. The affected motor cortex of the other half rats in each group was separated under anesthesia and used to detect the expressions of brain-derived neurotrophic factor (BDNF), SDF1, and CXCR4. Motor function was tested by a ladder-climbing test before and after the experiment. HBOT significantly enhanced neurogenesis in the penumbra area and promoted the expressions of SDF1 and CXCR4. The numbers of BrdU+/SDF1+, BrdU+/CXCR4+, and BrdU+/NeuN+ cells and BDNF concentrations in the penumbra were all significantly increased in the HBO group when compared with the control group. The motor functions were improved in both groups, but there was a significant difference between groups in the post-test. Our results indicated that HBOT for 21 days enhanced neurogenesis and promoted cell migration toward the penumbra area in transient brain ischemic rats. HBOT also increased BDNF expression, which might further promote the reconstructions of the impaired neural networks and restore motor function.

Extracellular Matrix Biomimetic Hydrogels, Encapsulated with Stromal Cell-Derived Factor 1, Improve the Composition of Foetal Tissue Grafts in a Rodent Model of Parkinson's Disease.

Clinical studies have provided evidence for dopamine (DA) cell replacement therapy in Parkinson's Disease. However, grafts derived from foetal tissue or pluripotent stem cells (PSCs) remain heterogeneous, with a high proportion of non-dopaminergic cells, and display subthreshold reinnervation of target tissues, thereby highlighting the need to identify new strategies to improve graft outcomes. In recent work, Stromal Cell-Derived Factor-1 (SDF1), secreted from meninges, has been shown to exert many roles during ventral midbrain DA development and DA-directed differentiation of PSCs. Related, co-implantation of meningeal cells has been shown to improve neural graft outcomes, however, no direct evidence for the role of SDF1 in neural grafting has been shown. Due to the rapid degradation of SDF1 protein, here, we utilised a hydrogel to entrap the protein and sustain its delivery at the transplant site to assess the impact on DA progenitor differentiation, survival and plasticity. Hydrogels were fabricated from self-assembling peptides (SAP), presenting an epitope for laminin, the brain's main extracellular matrix protein, thereby providing cell adhesive support for the grafts and additional laminin-integrin signalling to influence cell fate. We show that SDF1 functionalised SAP hydrogels resulted in larger grafts, containing more DA neurons, increased A9 DA specification (the subpopulation of DA neurons responsible for motor function) and enhanced innervation. These findings demonstrate the capacity for functionalised, tissue-specific hydrogels to improve the composition of grafts targeted for neural repair.

Regulation of the thrombin/protease-activated receptor 1 axis by chemokine (CXC motif) receptor 4.

The chemokine receptor CXCR4, a G protein-coupled receptor (GPCR) capable of heteromerizing with other GPCRs, is involved in many processes, including immune responses, hematopoiesis, and organogenesis. Evidence suggests that CXCR4 activation reduces thrombin/protease-activated receptor 1 (PAR1)-induced impairment of endothelial barrier function. However, the mechanisms underlying cross-talk between CXCR4 and PAR1 are not well-understood. Using intermolecular bioluminescence resonance energy transfer and proximity ligation assays, we found that CXCR4 heteromerizes with PAR1 in the HEK293T expression system and in human primary pulmonary endothelial cells (hPPECs). A peptide analog of transmembrane domain 2 (TM2) of CXCR4 interfered with PAR1:CXCR4 heteromerization. In HTLA cells, the presence of CXCR4 reduced the efficacy of thrombin to induce ß-arrestin-2 recruitment to recombinant PAR1 and enhanced thrombin-induced Ca2+ mobilization. Whereas thrombin-induced extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation occurred more transiently in the presence of CXCR4, peak ERK1/2 phosphorylation was increased when compared with HTLA cells expressing PAR1 alone. CXCR4-associated effects on thrombin-induced ß-arrestin-2 recruitment to and signaling of PAR1 could be reversed by TM2. In hPPECs, TM2 inhibited thrombin-induced ERK1/2 phosphorylation and activation of Ras homolog gene family member A. CXCR4 siRNA knockdown inhibited thrombin-induced ERK1/2 phosphorylation. Whereas thrombin stimulation reduced surface expression of PAR1, CXCR4, and PAR1:CXCR4 heteromers, chemokine (CXC motif) ligand 12 stimulation reduced surface expression of CXCR4 and PAR1:CXCR4 heteromers, but not of PAR1. Finally, TM2 dose-dependently inhibited thrombin-induced impairment of hPPEC monolayer permeability. Our findings suggest that CXCR4:PAR1 heteromerization enhances thrombin-induced G protein signaling of PAR1 and PAR1-mediated endothelial barrier disruption.

Stromal cell-derived factor-1 promotes osteoblastic differentiation of human bone marrow mesenchymal stem cells via the lncRNA-H19/miR-214-5p/BMP2 axis.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1) plays an important role in the osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBMMSCs), but the specific mechanism remains unclear. Our study aimed to clarify the role of the lncRNA-H19/miR-214-5p/BMP2 axis in the osteoblastic differentiation of hBMMSCs induced by SDF-1. METHODS: We used reverse-transcriptase polymerase chain reaction, western blotting, alkaline phosphatase activity test, and Alizarin red staining to evaluate the osteoblastic differentiation of primary hBMMSCs and the luciferase reporter assay to determine if lncRNA-H19 binds with miR-214-5p. RESULTS: Our results indicated that SDF-1 (50 ng/mL) promotes the osteoblastic differentiation of hBMMSCs, significantly upregulates osteoblastogenic genes (OCN, OSX, RUNX2, and ALP), and increases Alizarin red staining, alkaline phosphatase activity, and lncRNA-H19 expression. Luciferase reporter assay verified that lncRNA-H19 binds with and represses miR-214-5p, thereby upregulating BMP2 expression. Use of miR-214-5p inhibitor or overexpression of lncRNA-H19 can promote the osteoblastic differentiation of hBMMSCs, but miR-214-5p or shH19 inhibits the osteoblastic differentiation of hBMMSCs. Treatment with an miR-214-5p inhibitor could rescue the inhibitory effect of shH19 on the osteoblastic differentiation of hBMMSCs. CONCLUSIONS: Taken together, SDF-1 promotes the osteoblastic differentiation of hBMMSCs through the lncRNA-H19/miR-214-5p/BMP2 axis. Increased osteoblastic differentiation by an miR-214-5p inhibitor reveals a new possible strategy for the treatment of bone defect and osteoporosis.

Tuning the network charge of biohybrid hydrogel matrices to modulate the release of SDF-1.

The delivery of chemotactic signaling molecules via customized biomaterials can effectively guide the migration of cells to improve the regeneration of damaged or diseased tissues. Here, we present a novel biohybrid hydrogel system containing two different sulfated glycosaminoglycans (sGAG)/sGAG derivatives, namely either a mixture of short heparin polymers (Hep-Mal) or structurally defined nona-sulfated tetrahyaluronans (9s-HA4-SH), to precisely control the release of charged signaling molecules. The polymer networks are described in terms of their negative charge, i.e. the anionic sulfate groups on the saccharides, using two parameters, the integral density of negative charge and the local charge distribution (clustering) within the network. The modulation of both parameters was shown to govern the release characteristics of the chemotactic signaling molecule SDF-1 and allows for seamless transitions between burst and sustained release conditions as well as the precise control over the total amount of delivered protein. The obtained hydrogels with well-adjusted release profiles effectively promote MSC migration in vitro and emerge as promising candidates for new treatment modalities in the context of bone repair and wound healing.

The role of stromal cell-derived factor 1 on cartilage development and disease.

Stromal cell-derived factor 1 (SDF-1), also known as CXC motif chemokine ligand 12 (CXCL12), is recognized as a homeostatic cytokine with strong chemotactic potency. It plays an important role in physiological and pathological processes, such as the development of multiple tissues and organs, the regulation of cell distribution, and tumour metastasis. SDF-1 has two receptors, CXC chemokine receptor type 4 (CXCR4) and CXC chemokine receptor type 7 (CXCR7). SDF-1 affects the proliferation, survival, differentiation and maturation of chondrocytes by binding to CXCR4 on chondrocytes. Therefore, SDF-1 has been used as an exogenous regulatory target in many studies to explore the mechanism of cartilage development. SDF-1 is also a potential therapeutic target for osteoarthritis (OA) and rheumatoid arthritis (RA), because of its role in pathological initiation and regulation. In addition, SDF-1 shows potent capacity in the repair of cartilage defects by recruiting endogenous stem cells in a cartilage tissue engineering context. To summarize the specific role of SDF-1 on cartilage development and disease, all articles had been screened out in PubMed by May 30, 2020. The search was limited to studies published in English. Search terms included SDF-1; CXCL12; CXCR4; chondrocyte; cartilage; OA; RA, and forty-seven papers were studied. Besides, we reviewed references in the articles we searched to get additional relevant backgrounds. The review aims to conclude the current knowledge regarding the physiological and pathological role of SDF-1 on the cartilage and chondrocyte. More investigations are required to determine methods targeted SDF-1 to cartilage development and interventions to cartilage diseases.

Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial.

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.

SDF-1 mediates mesenchymal stem cell recruitment and migration via the SDF-1/CXCR4 axis in bone defect.

INTRODUCTION: Recent studies have indicated the potential of stem cell therapy in combination with cytokines to restore the bone repair via migration and homing of stem cells to the defected area. The present study aimed to investigate the mobilization and recruitment of mesenchymal stem cells (MSCs) in response to SDF-1. MATERIALS AND METHODS: Herein, the knockout rat model of the bone defect (BD) was treated with the induced membrane technique. Then, wild type Wistar rats and SDF-1-knockout rats were selected for the establishment of BD-induced membrane (BD-IM) models and bone-graft (BG) models. The number of MSCs was evaluated by flow cytometry, along with the expression pattern of the SDF-1/CXCR4 axis as well as osteogenic factors was identified by RT-qPCR and Western blot analyses. Finally, the MSC migration ability was assessed by the Transwell assay. RESULTS: Our data illustrated that in the induced membrane tissues, the number of MSCs among the BD-IM modeled rats was increased, whereas, a lower number was documented among BG modeled rats. Besides, we found that lentivirus-mediated over-expression of SDF-1 in BG modeled rats could activate the SDF-1/CXCR4 axis, mobilize MSCs into the defect area, and up-regulate the osteogenic proteins. CONCLUSIONS: Collectively, our study speculated that up-regulation of SDF-1 promotes the mobilization and migration of MSCs through the activation of the SDF-1/CXCR4 signal pathway.

SDF-1 modulates periodontal ligament-Mesenchymal Stem Cells (pdl-MSCs).

BACKGROUND/OBJECTIVES: In this in vitro study, the effects of Stromal cell-derived factor-1 (SDF-1) was evaluated on the periodontal ligament-Mesenchymal Stem Cells (pdl-MSCs) functions. MATERIAL AND METHODS: Real-time cell analyzer-single plate (RTCA-SP) was employed for proliferation, and RTCA-dual purpose (DP) was utilized for pdl-MSCs migration potential treated with different SDF-1 concentrations (0, 0.1, 1, 10, 100, 200, and 400 ng/ml). Based on the dose-response findings, 10 ng/ml SDF-1 was used for further mRNA experiments. RNAs isolated at 6 and 24 h were checked using quantitative RT-PCR for mineralized tissue-associated genes including type I collagen (COL I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (Runx2). cRNA was synthesized for 6 h, and whole-genome array analysis was performed for over 47.000 probes. Data were subjected to quantile normalization before analysis. RESULTS: Increased proliferation and migration were observed in pdl-MSCs treated with 0.1, 1, and 10 ng/ml SDF-1. Increased COL I was observed at both time points: 6 and 24 h. While there was no significant change for OCN, OPN, and Runx2 at 6 h, SDF-1 up-regulated OCN and OPN, but down-regulated Runx2 mRNA expressions at 24 h. IL-8 and ESM1 genes were differentially expressed over twofold when the pdl-MSCs were exposed to SDF-1 at whole-genome array analysis. IL-8 induction was confirmed with RT-PCR. CONCLUSION: Findings of this study displayed that SDF-1 modulated pdl-MSCs which were important for periodontal regeneration, inducing migration and proliferation, and regulating extracellular matrix synthesis in favor of the formation of new attachment.