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Low‐energy shock wave (LESW) has been recognized as a promising non‐invasive intervention to prevent the organs or tissues against ischaemia reperfusion injury (IRI), whereas its effect on kidney injury is rarely explored. To investigate the protective role of pretreatment with LESW on renal IRI in rats, animals were randomly divided into Sham, LESW, IRI and LESW + IRI groups. At 4, 12, 24 hours and 3 and 7 days after reperfusion, serum samples and renal tissues were harvested for performing the analysis of renal function, histopathology, immunohistochemistry, flow cytometry and Western blot, as well as enzyme‐linked immunosorbent assay. Moreover, circulating endothelial progenitor cells (EPCs) were isolated, labelled with fluorescent dye and injected by tail vein. The fluorescent signals of EPCs were detected using fluorescence microscope and in vivo imaging system to track the distribution of injected circulating EPCs. Results showed that pretreatment with LESW could significantly reduce kidney injury biomarkers, tubular damage, and cell apoptosis, and promote cell proliferation and vascularization in IRI kidneys. The renoprotective role of LESW pretreatment would be attributed to the remarkably increased EPCs in the treated kidneys, part of which were recruited from circulation through SDF‐1/CXCR7 pathway. In conclusion, pretreatment with LESW could increase the recruitment of circulating EPCs to attenuate and repair renal IRI.

Despite improvements in therapy and management, cancer represents and remains a major cause of mortality and morbidity worldwide. Although genetics serve an important role in tumorigenesis and tumour progression, the tumour microenvironment (TME) in solid tumours is also important and has been indicated to contribute to these processes. Stromal cell-derived factors (SDFs) represent an important family within the TME. The family includes SDF-1, SDF-2, SDF2-like 1 (SDF2L1), SDF-3, SDF-4 and SDF-5. SDF-1 has been demonstrated to act as a positive regulator in a number of types of tumour, such as oesophago-gastric, pancreatic, lung, breast, colorectal and ovarian cancer, while the biology and functions of other members of the SDF family, including SDF-2, SDF2L1, SDF-4 and SDF-5, in cancer are different, complex and controversial, and remain mainly unknown. Full identification and understanding of the SDFs across multiple types of cancer is required to elucidate their function and establish potential key targets in cancer.

Human breast carcinoma‐associated fibroblasts (CAFs) increasingly acquire both transforming growth factor‐β (TGF‐β) and stromal cell‐derived factor‐1 (SDF‐1) signaling in an autocrine fashion during tumor progression. Such signaling mediates activated myofibroblastic and tumor‐promoting properties in these fibroblasts. CD26/dipeptidyl peptidase‐4 is a serine protease that cleaves various chemokines including SDF‐1. Stromal CD26 expression is reportedly undetectable in human skin squamous cell carcinomas. However, whether stromal CD26 expression is also downregulated in human breast cancers and which stromal cells potentially lack CD26 expression remain elusive. To answer these questions, sections prepared from 239 human breast carcinomas were stained with antibodies against CD26 and α‐smooth muscle actin (α‐SMA), a marker for activated myofibroblasts. We found that tumor‐associated stroma involving α‐SMA‐positive myofibroblasts stained negative or negligible for CD26 in 118 out of 193 (61.1%) tumors, whereas noncancerous stromal regions of the breast showed considerable staining for CD26. This decreased stromal CD26 staining in tumors also tends to be associated with poor outcomes for breast cancer patients. Moreover, we demonstrated that CD26 staining is attenuated on stromal myofibroblasts in human breast cancers. Consistently, CD26 expression is significantly downregulated in cultured CAF myofibroblasts extracted from human breast carcinomas as compared to control human mammary fibroblasts. Inhibition of TGF‐β or SDF‐1 signaling in CAFs by shRNA clearly upregulated the CD26 expression. Taken together, these findings indicate that CD26 expression is attenuated by TGF‐β‐ and SDF‐1‐autocrine signaling on stromal myofibroblasts in human mammary carcinomas, and that decreased stromal CD26 expression has potential as a prognostic marker. Human breast carcinoma‐associated fibroblasts (CAFs) increasingly acquire both transforming growth factor‐β (TGF‐β) and stromal cell‐derived factor‐1 (SDF‐1) signaling in an autocrine fashion during tumor progression. We found that CD26 expression is attenuated by TGF‐β‐ and SDF‐1‐autocrine signaling on stromal myofibroblasts in human mammary carcinomas, and that decreased stromal CD26 expression has potential as a potential prognostic marker.

Previous studies confirmed that stromal cell‐derived factor 1 (SDF‐1) was a principal regulator of retention, migration and mobilization of haematopoietic stem cells and endothelial progenitor cells (EPCs) during steady‐state homeostasis and injury. CXC chemokine receptor 4 (CXCR4) has been considered as the unique receptor of SDF‐1 and as the only mediator of SDF‐1‐induced biological effects for many years. However, recent studies found that SDF‐1 could bind to not only CXCR4 but also CXC chemokine receptor 7 (CXCR7). The evidence that SDF‐1 binds to the CXCR7 raises a concern how to distinguish the potential contribution of the SDF‐1/CXCR7 pathway from SDF‐1/CXCR4 pathway in all the processes that were previously attributed to SDF‐1/CXCR4. In this study, the role of CXCR7 in EPCs was investigated in vitro. RT‐PCR, Western blot and flow cytometry assay demonstrate that both CXCR4 and CXCR7 were expressed highly in EPCs. The adhesion of EPCs induced by SDF‐1 was inhibited by blocking either CXCR4 or CXCR7 with their antibodies or antagonists. SDF‐1 regulated the migration of EPCs via CXCR4 but not CXCR7. However, the transendothelial migration of EPCs was inhibited by either blocking of CXCR4 or CXCR7. Both CXCR7 and CXCR4 are essential for the tube formation of EPCs induced by SDF‐1. These results suggested that both CXCR7 and CXCR4 are important for EPCs in response to SDF‐1, indicating that CXCR7 may be another potential target molecule for angiogenesis‐dependent diseases.

Treatment of myocardial infarction (MI) remains a major challenge. The chemokine family plays an important role in cardiac injury, repair, and remodeling following MI, while stromal cell‐derived factor‐1 alpha (SDF‐1α) is the most promising therapeutic target. This study aimed to increase SDF‐1α expression using a novel gene delivery system and further explore its effect on MI treatment. In this study, two kinds of plasmids, human SDF‐1α plasmid (phSDF‐1α) and human SDF‐1α‐ nuclear factor κB plasmid (phSDF‐1α‐NFκB), were constructed and loaded onto cationic microbubble carriers, and the plasmids were released into MI rabbits by ultrasound‐targeted microbubble destruction. The transfection efficiency of SDF‐1α and the degree of heart repair were further explored and compared. In the MI rabbit models, transfection with phSDF‐1α‐NFκB resulted in higher SDF‐1α expression in peri‐infarct area compared with transfection with phSDF‐1α or no transfection. Upregulation of SDF‐1α was shown beneficial to these MI rabbit models, as demonstrated with better recovery of cardiac function, greater perfusion of the myocardium, more neovascularization, smaller infarction size and thicker infarct wall 1 month after treatment. Ultrasound‐targeted cationic microbubbles combined with the NFκB binding motif could increase SDF‐1α gene transfection, which would play a protective role after MI.

Aberrant chemokine stromal cell‐derived factor 1 (SDF‐1) expression has been shown to be involved in the development and progression of various malignancies. Our present study aims to investigate the clinical and prognostic value of SDF‐1 expression and improve risk stratification in patients with gastric cancer. Peritumoral and intratumoral SDF‐1 levels were assessed in 220 retrospectively enrolled gastric cancer patients, and their relations with clinicopathological features and clinical outcomes were evaluated. A predictive nomogram was created to refine risk stratification for overall survival of gastric cancer patients. Compared with peritumor tissues, tumor tissues showed decreased SDF‐1 expression levels according to TNM stage progression in gastric cancer specimens. Peritumoral SDF‐1 expression correlated positively with tumor invasion depth and lymph node metastasis, whereas intratumoral SDF‐1 expression associated negatively with tumor size, tumor differentiation, tumor invasion depth, lymph node metastasis, and clinical TNM stage. Moreover, both low peritumoral SDF‐1 expression and high intratumoral SDF‐1 expression indicated favorable overall survival, and SDF‐1 risk derived from the peritumoral/intratumoral SDF‐1 expression signature could stratify prognosis of patients with gastric cancer. After backward elimination, SDF‐1 risk was identified as an independent prognostic factor for survival. Finally, a predictive nomogram was generated with identified independent prognosticators to assess patient survival at 3 and 5 years following surgery. Conclusively, SDF‐1 risk, an identified independent prognostic factor, could be developed into a nomogram with tumor invasion depth, lymph node involvement, and distant metastasis to refine predictive accuracy for survival in patients with gastric cancer after surgical resection. We derived a SDF‐1 expression based risk stratification system from the peritumoral/intratumoral SDF‐1 expression signature. The SDF‐1 risk, identified as an independent prognostic factor, could be developed into a nomogram with tumor invasion depth, lymph node involvement, and distant metastasis to refine predictive accuracy for survival in patients with gastric cancer after surgical resection.

Mesenchymal stromal cells (MSCs) have a supportive role in hematopoiesis and as components of the bone marrow (BM) microenvironment may present alterations during acute lymphoblastic leukemia (ALL) and be affected by chemotherapeutic agents. We examined the biological and functional characteristics of MSCs in ALL diagnosis and treatment and their effect on MSC qualitative properties. Immunophenotypic characterization, evaluation of clonogenicity, and proliferative capacity were measured. Apoptotic features, cell-cycle analysis, and stromal cell-derived factor 1α and angiopoietin-1 levels in MSC supernatant at diagnosis and in different phases of treatment were assessed. Chemotherapy was administered according to the Berlin-Frankfurt-Munster-2000 protocol. BM samples from children with solid tumors without BM involvement were used as the control group. The morphology, the immunophenotypic profile, and the apoptotic characteristics of the MSCs were not affected by leukemia. The secretion of factors involved in the trafficking of hematopoietic cells in the BM seems to be upregulated at diagnosis in comparison to the treatment phases. MSCs are influenced by the disease in terms of their functional characteristics such as clonogenicity and proliferation rate. These effects cease as soon as treatment is initiated. Chemotherapy does not seem to exert any effect on any of the MSC features examined. MSCs from children with ALL are affected by their interaction with the leukemic environment, but this phenomenon ceases upon treatment initiation, while no effect is observed by chemotherapy itself.

The role of neutrophils in bone regeneration remains elusive. In this study, it is shown that intramuscular implantation of interleukin‐8 (IL‐8) (commonly recognized as a chemotactic cytokine for neutrophils) at different levels lead to outcomes resembling those of fracture hematoma at various stages. Ectopic endochondral ossification is induced by certain levels of IL‐8, during which neutrophils are recruited to the implanted site and are N2‐polarized, which then secrete stromal cell‐derived factor‐1α (SDF‐1α) for bone mesenchymal stem cell (BMSC) chemotaxis via the SDF‐1/CXCR4 (C‐X‐C motif chemokine receptor 4) axis and its downstream phosphatidylinositol 3'‐kinase (PI3K)/Akt pathway and β‐catenin‐mediated migration. Neutrophils are pivotal for recruiting and orchestrating innate and adaptive immunocytes, as well as BMSCs at the initial stage of bone healing and regeneration. The results in this study delineate the mechanism of neutrophil‐initiated bone regeneration and interaction between neutrophils and BMSCs, and innate and adaptive immunities. This work lays the foundation for research in the fields of bone regenerative therapy and biomaterial development, and might inspire further research into novel therapeutic options. Following inflammatory stimuli at the bone defect site, neutrophils arrive first, recruit and orchestrate innate and adaptive immunocytes and BMSCs to initiate endochondral ossification under the appropriate immune environment. In this process, N2‐polarized neutrophils mediate anti‐inflammatory transformation of macrophages and CD4+ T cells, secrete SDF‐1α for BMSC chemotaxis via the SDF‐1/CXCR4 axis and its downstream PI3K/AKT pathway and β‐catenin‐mediated migration.

Objectives Stromal cell‐derived factor‐1 (SDF‐1) actively directs endogenous cell homing. Exendin‐4 (EX‐4) promotes stem cell osteogenic differentiation. Studies revealed that EX‐4 strengthened SDF‐1‐mediated stem cell migration. However, the effects of SDF‐1 and EX‐4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo. Methods Cell‐counting kit‐8 (CCK8), transwell assay, qRT‐PCR and western blot were used to determine the effects and mechanism of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF‐1 and systemic injection of EX‐4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo. Results SDF‐1/EX‐4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis‐related gene expression compared to SDF‐1 or EX‐4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF‐1/EX‐4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF‐1/EX‐4 cotherapy significantly promoted new bone formation, recruited more CXCR4+ cells and CD90+/CD34‐ stromal cells to the defects, enhanced early‐stage osteoclastogenesis and osteogenesis‐related markers expression in regenerated bone compared to control, SDF‐1 or EX‐4 in vivo. Conclusions SDF‐1/EX‐4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration. Locally delivered stromal cell‐derived factor‐1 (SDF‐1) combined with systemically applied Exendin‐4 (EX‐4) synergestically recruited endogenous stem cells towards the rat periodontal defects. Further, the cotherapy enhanced the proliferation and osteogenic differentiation of the engrafted stem cells in coordination, thus significantly facilitated periodontal bone regeneration.

Bone defects resulting from non‐union fractures or tumour resections are common clinical problems. Long non‐coding RNAs (lncRNAs) are reported to play vital roles in stem cell differentiation. The aim of this study was to elucidate the role of lncRNA‐H19 in osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Following the establishment of an osteogenic differentiation model in rats, the expression of H19, microRNA‐149 (miR‐149) and stromal cell‐derived factor‐1 (SDF‐1) was measured by RT‐qPCR. Thereafter, BMMSCs were isolated from rats and treated with a series of mimic, inhibitor or siRNA. SDF‐1 expression, alkaline phosphatase (ALP) activity and osteocalcin (OCN) content were detected. The mineralized and calcified nodules were assessed by alizarin red S and Von Kossa staining. BMMSC surface markers were detected by flow cytometry. Western blot analysis was used to measure the expression of ALP, OCN, runt‐related transcription factor 2 (RUNX2) and osterix (OSX) proteins. Lastly, dual‐luciferase reporter gene assay and RNA immunoprecipitation were applied to verify the relationship of H19, miR‐149 and SDF‐1. Overexpressed H19 and SDF‐1 and poorly expressed miR‐149 were found in rats with osteogenic differentiation. H19 increased SDF‐1 expression by binding to miR‐149. H19 enhanced ALP activity, OCN content, calcium deposit and ALP, OCN, RUNX2 and OSX protein expression of BMMSCS by up‐regulating SDF‐1 via binding to miR‐149. Taken together, up‐regulated H19 could promote the osteogenic differentiation of BMMSCs by increasing SDF‐1 via miR‐149.