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Harnessing endogenous stem/progenitor cells to enhance extracellular matrix (ECM) deposition in the nucleus pulposus (NP) is considered as a potential treatment for intervertebral disc degeneration (IVDD), but is limited by the lack of suitable scaffolds for cell infiltration and growth, as well as the tailored release of bioactive factors. Herein, an injectable cell‐free microgel assembly (MA‐TNS) with interconnected microporous structure is developed to recruit stem/progenitor cells and induce the differentiation of the recruited cells by releasing stromal cell‐derived factor‐1α (SDF‐1α) and transforming growth factor‐β1 (TGF‐β1) sequentially. TGF‐β1 is initially loaded by the chondroitin sulfate/gelatin nanoparticles. Together with SDF‐1α, these nanoparticles are co‐encapsulated into the photo‐cross‐linked microgels, which are then assembled into a microporous scaffold via dynamic boronate ester bonds. An initial rapid release of SDF‐1α followed by a sustained release of TGF‐β1 lasting over 28 days is achieved. MA‐TNS significantly promotes the recruitment, infiltration, and chondrocyte‐like differentiation of marrow mesenchymal stem cells in vitro. Furthermore, in vivo experiments on rats and cynomolgus monkeys prove that MA‐TNS can inhibit IVDD and recover ECM deposition markedly, thereby enabling long‐term NP reconstruction. The resulting efficacy in rats and nonhuman primates supports that MA‐TNS is a promising scaffold for intervertebral disc repair and regeneration. [ABSTRACT FROM AUTHOR]

Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo , Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture. An injectable sodium alginate hydrogel was fabricated to codeliver and sustainably release Treg-Exo and SDF-1α, which facilitated fracture healing by the synergistic effect of Treg-Exo-mediated macrophage polarization and SDF-1α-mediated MSC recruitment. [Display omitted] • Microfluidic chips were used to isolate CD39 and CD73 expressing Treg-derived exosomes (Treg-Exo). • Treg-Exo expressing CD39 and CD73 catalyzed ATP hydrolysis and promoted M2 macrophage polarization via AC/cAMP/PKA/CREB pathway. • Treg-Exo-primed M2 macrophages promoted the proliferation and osteogenesis of BMSCs. • An injectable hydrogel was constructed to co-deliver Treg-Exo and SDF-1α to exert the synergistic effect of macrophage polarization and MSCs recruitment. [ABSTRACT FROM AUTHOR]

A three‐dimensional alginate‐coated scaffold (GAIS) was constructed in the present study to showcase the multidifferentiation potential of peripheral blood mesenchymal stem cells (PBMSCs) and to investigate the role and mechanism by which Icariin (ICA)/stromal cell‐derived factor (SDF‐1α)/PBMSCs promote damaged articular repair. In addition, the ability of ICA, in combination with SDF‐1α, to promote the migration and proliferation of stem cells was validated through the utilization of CCK‐8 and migration experiments. The combination of ICA and SDF‐1α inhibited the differentiation of PBMSCs into cartilage, as demonstrated by in vivo experiments and histological staining. Both PCR and western blot experiments showed that GAIS could upregulate the expression of particular genes in chondrocytes. In comparison to scaffolds devoid of alginate (G0), PBMSCs seeded into GAIS scaffolds exhibited a greater rate of proliferation, and the conditioned medium derived from scaffolds containing SDF‐1α enhanced the capacity for cell migration. Moreover, after a 12‐week treatment period, GAIS, when successfully transplanted into osteochondral defects of mice, was found to promote cartilage regeneration and repair. The findings, therefore, demonstrate that GAIS enhanced the in vitro capabilities of PBMSCs, including proliferation, migration, homing and chondrogenic differentiation. In addition, ICA and SDF‐1α effectively collaborated to support cartilage formation in vivo. Thus, the ICA/SDF‐1α/PBMSC‐loaded biodegradable alginate‐gelatin scaffolds showcase considerable potential for use in cartilage repair. [ABSTRACT FROM AUTHOR]

Abstract Background The long-term nonunion of bone defects is always a difficult problem in orthopaedics treatment. Artificial bone implants made of polymeric materials are expected to solve this problem due to their suitable degradation rate and good biocompatibility. However, the lack of mechanical strength, low osteogenic induction ability and poor hydrophilicity of these synthetic polymeric materials limit their large-scale clinical application. Results In this study, we used bioactive glass (BG) (20%, W/W) and polycaprolactone (PCL, 80%, W/W) as raw materials to prepare a bone repair scaffold (PCL@BG20) using fused deposition modelling (FDM) three-dimensional (3D) printing technology. Subsequently, stromal cell-derived factor-1α (SDF-1α) chemokines were loaded into the PCL@BG20 scaffold pores with gelatine methacryloyl (GelMA) hydrogel. The experimental results showed that the prepared scaffold had a porous biomimetic structure mimicking that of cancellous bone, and the compressive strength (44.89 ± 3.45 MPa) of the scaffold was similar to that of cancellous bone. Transwell experiments showed that scaffolds loaded with SDF-1α could promote the recruitment of bone marrow stromal cells (BMSCs). In vivo data showed that treatment with scaffolds containing SDF-1α and BG (PCL@BG-GelMA/SDF-1α) had the best effect on bone defect repair compared to the other groups, with a large amount of new bone and mature collagen forming at the bone defect site. No significant organ toxicity or inflammatory reactions were observed in any of the experimental groups. Conclusions The results show that this kind of scaffold containing BG and SDF-1α serves the dual functions of recruiting stem cell migration in vivo and promoting bone repair in situ. We envision that this scaffold may become a new strategy for the clinical treatment of bone defects.

Abstract Aims We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. Methods and results Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7‐nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad‐shSDF‐1α into the infarcted heart. Cardiac tissue acetylcholine (ACh) and serum ACh, tumour necrosis factor α (TNF‐α), interleukin 1β (IL‐1β) and interleukin 6 (IL‐6) levels were detected by ELISA to determine whether VNS was successful. An inflammatory injury model in human coronary artery endothelial cells (HCAECs) was established by lipopolysaccharide and identified by evaluating TNF‐α, IL‐1β and IL‐6 levels and tube formation. Immunohistochemistry staining was performed to evaluate CD31‐positive vessel density and stromal cell‐derived factor‐l alpha (SDF‐1α) expression in the MI heart in vivo and the expression and distribution of SDF‐1α, C‐X‐C motif chemokine receptor 4 and CXCR7 in HCAECs in vitro. Western blotting was used to detect the levels of SDF‐1α, V‐akt murine thymoma viral oncogene homolog (AKT), phosphorylated AKT (pAKT), specificity protein 1 (Sp1) and phosphorylation of Sp1 in HCAECs. Left ventricular performance, including left ventricular systolic pressure, left ventricular end‐diastolic pressure and rate of the rise and fall of ventricular pressure, should be evaluated 28 days after VNS treatment. VNS was successfully established for MI therapy with decreases in serum TNF‐α, IL‐1β and IL‐6 levels and increases in cardiac tissue and serum ACh levels, leading to increased SDF‐1α expression in coronary endothelial cells of MI hearts, triggering angiogenesis of MI hearts with increased CD31‐positive vessel density, which was abolished by the m/nAChR inhibitors mecamylamine and atropine or knockdown of SDF‐1α by shRNA. ACh promoted SDF‐1α expression and its distribution along with the branch of the formed tube in HCAECs, resulting in an increase in the number of tubes formed in HCAECs. ACh increased the levels of pAKT and phosphorylation of Sp1 in HCAECs, resulting in inducing SDF‐1α expression, and the specific effects could be abolished by mecamylamine, atropine, the PI3K/AKT blocker wortmannin or the Sp1 blocker mithramycin. Functionally, VNS improved left ventricular performance, which could be abolished by Ad‐shSDF‐1α. Conclusions VNS promoted angiogenesis to repair the infarcted heart by inducing SDF‐1α expression and redistribution along new branches during angiogenesis, which was associated with the m/nAChR‐AKT‐Sp1 signalling pathway.

Introduction: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft‐tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. Aim: The aim of this project was to assess plasmatic biomolecules indicative of osteo‐cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. Methods: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. Results: Two biomarkers were identified, respectively SDF‐1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. Conclusion: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy. [ABSTRACT FROM AUTHOR]

Vagal nerve stimulation (VNS) provides a novel therapeutic strategy for injured hearts by activating cholinergic anti-inflammatory pathways. However, little information is available on the metabolic pattern and arteriogenesis of VSMCs after MI. VNS has been shown to stimulate the expression of CPT1α, CPT1β, Glut1, Glut4 and SDF-1α in coronary VSMCs, decreasing the number of CD68-positive macrophages while increasing CD206-positive macrophages in the infarcted hearts, leading to a decrease in TNF-α and IL-1β accompanied by a reduced ratio of CD68- and CD206-positive cells, which were dramatically abolished by atropine and mecamylamine in vivo. Knockdown of SDF-1α substantially abrogated the effect of VNS on macrophagecell alteration and inflammatory factors in infarcted hearts. Mechanistically, ACh induced SDF-1α expression in VSMCs in a dose-dependent manner. Conversely, atropine, mecamylamine, and a PI3K/Akt inhibitor completely eliminated the effect of ACh on SDF-1α expression. Functionally, VNS promoted arteriogenesis and improved left ventricular performance, which could be abolished by Ad-shSDF-1α. Thus, VNS altered the VSMC metabolism pattern and arteriogenesis to repair the infarcted heart by inducing SDF-1α expression, which was associated with the m/nAChR-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The long-term nonunion of bone defects is always a difficult problem in orthopaedics treatment. Artificial bone implants made of polymeric materials are expected to solve this problem due to their suitable degradation rate and good biocompatibility. However, the lack of mechanical strength, low osteogenic induction ability and poor hydrophilicity of these synthetic polymeric materials limit their large-scale clinical application. Results: In this study, we used bioactive glass (BG) (20%, W/W) and polycaprolactone (PCL, 80%, W/W) as raw materials to prepare a bone repair scaffold (PCL@BG20) using fused deposition modelling (FDM) three-dimensional (3D) printing technology. Subsequently, stromal cell-derived factor-1α (SDF-1α) chemokines were loaded into the PCL@BG20 scaffold pores with gelatine methacryloyl (GelMA) hydrogel. The experimental results showed that the prepared scaffold had a porous biomimetic structure mimicking that of cancellous bone, and the compressive strength (44.89 ± 3.45 MPa) of the scaffold was similar to that of cancellous bone. Transwell experiments showed that scaffolds loaded with SDF-1α could promote the recruitment of bone marrow stromal cells (BMSCs). In vivo data showed that treatment with scaffolds containing SDF-1α and BG (PCL@BG-GelMA/SDF-1α) had the best effect on bone defect repair compared to the other groups, with a large amount of new bone and mature collagen forming at the bone defect site. No significant organ toxicity or inflammatory reactions were observed in any of the experimental groups. Conclusions: The results show that this kind of scaffold containing BG and SDF-1α serves the dual functions of recruiting stem cell migration in vivo and promoting bone repair in situ. We envision that this scaffold may become a new strategy for the clinical treatment of bone defects. [ABSTRACT FROM AUTHOR]

Aims: We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. Methods and results: Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7‐nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad‐shSDF‐1α into the infarcted heart. Cardiac tissue acetylcholine (ACh) and serum ACh, tumour necrosis factor α (TNF‐α), interleukin 1β (IL‐1β) and interleukin 6 (IL‐6) levels were detected by ELISA to determine whether VNS was successful. An inflammatory injury model in human coronary artery endothelial cells (HCAECs) was established by lipopolysaccharide and identified by evaluating TNF‐α, IL‐1β and IL‐6 levels and tube formation. Immunohistochemistry staining was performed to evaluate CD31‐positive vessel density and stromal cell‐derived factor‐l alpha (SDF‐1α) expression in the MI heart in vivo and the expression and distribution of SDF‐1α, C‐X‐C motif chemokine receptor 4 and CXCR7 in HCAECs in vitro. Western blotting was used to detect the levels of SDF‐1α, V‐akt murine thymoma viral oncogene homolog (AKT), phosphorylated AKT (pAKT), specificity protein 1 (Sp1) and phosphorylation of Sp1 in HCAECs. Left ventricular performance, including left ventricular systolic pressure, left ventricular end‐diastolic pressure and rate of the rise and fall of ventricular pressure, should be evaluated 28 days after VNS treatment. VNS was successfully established for MI therapy with decreases in serum TNF‐α, IL‐1β and IL‐6 levels and increases in cardiac tissue and serum ACh levels, leading to increased SDF‐1α expression in coronary endothelial cells of MI hearts, triggering angiogenesis of MI hearts with increased CD31‐positive vessel density, which was abolished by the m/nAChR inhibitors mecamylamine and atropine or knockdown of SDF‐1α by shRNA. ACh promoted SDF‐1α expression and its distribution along with the branch of the formed tube in HCAECs, resulting in an increase in the number of tubes formed in HCAECs. ACh increased the levels of pAKT and phosphorylation of Sp1 in HCAECs, resulting in inducing SDF‐1α expression, and the specific effects could be abolished by mecamylamine, atropine, the PI3K/AKT blocker wortmannin or the Sp1 blocker mithramycin. Functionally, VNS improved left ventricular performance, which could be abolished by Ad‐shSDF‐1α. Conclusions: VNS promoted angiogenesis to repair the infarcted heart by inducing SDF‐1α expression and redistribution along new branches during angiogenesis, which was associated with the m/nAChR‐AKT‐Sp1 signalling pathway. [ABSTRACT FROM AUTHOR]

Fracture nonunion remains a great challenge for orthopedic surgeons. Fracture repair comprises of three phases, the inflammatory, repair and remodeling stage. Extensive advancements have been made in the field of bone repair, including development of strategies to balance the M1/M2 macrophage populations, and to improve osteogenesis and angiogenesis. However, such developments focused on only one or the latter two phases, while ignoring the inflammatory phase during which cell recruitment occurs. In this study, we combined Stromal Cell-Derived Factor-1α (SDF-1α) and M2 macrophage derived exosomes (M2D-Exos) with a hyaluronic acid (HA)-based hydrogel precursor solution to synthesize an injectable, self-healing, adhesive HA@SDF-1α/M2D-Exos hydrogel. The HA hydrogel demonstrated good biocompatibility and hemostatic ability, with the 4% HA hydrogels displaying great antibacterial activity against gram-negative E. coli and gram-positive S. aureus and Methicillin-resistant Staphylococcus aureus (MRSA). Synchronously and sustainably released SDF-1α and M2D-Exos from the HA@SDF-1α/M2D-Exos hydrogel enhanced proliferation and migration of human bone marrow mesenchymal stem cell (HMSCs) and Human Umbilical Vein Endothelial Cells (HUVECs), promoting osteogenesis and angiogenesis both in vivo and in vitro. Overall, the developed HA@ SDF-1α/M2D-Exos hydrogel was compatible with the natural healing process of fractures and provides a new modality for accelerating bone repair by coupling osteogenesis, angiogenesis, and resisting infection at all stages.

Spinal Cord Injury (SCI), one of the major factors of disability, can cause irreversible motor and sensory impairment. There are no effective therapeutic drugs and technologies available in domestic or foreign countries currently. Neural stem cells (NSCs), with the potential for multidirectional differentiation, are a potential treatment for SCI. However, it has been demonstrated that NSCs primarily differentiated into astrocytes rather than neurons due to the inflammatory microenvironment, and the current challenge remains to direct the differentiation of NSCs into neurons in the lesion site. It was reported that the microtubule-stabilizing agent paclitaxel (PTX) was able to promote the differentiation of NSCs into neurons rather than astrocytes after SCI. SDF-1α can recruit NSCs and thus guide the migration of stem cells. In this study, we developed a functional collagen scaffold by loading SDF-1α and nanoparticleencapsulated PLGA-PTX into a 3D collagen porous scaffold, allowing for slow release of PTX. When the functional scaffolds were implanted into the injury site, it provided a neural regeneration conduit channel for the migration of NSCs and neuronal differentiation. Neural regeneration promoted the recovery of motor function and reduced glial scar formation after SCI. In conclusion, a 3D collagen porous scaffold combined with PLGA-PTX and SDF-1α is a promising therapeutic strategy for SCI repair. [ABSTRACT FROM AUTHOR]

Objective This study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric SLE (NPSLE). Methods We enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE. Results Based on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery–Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers homovanillic acid (HVA; P  = 0.0400), stromal cell-derived factor-1α (SDF-1α; P  = 0.0431) and stem cell growth factor-β (SCGF-1β; P  = 0.0061) were significantly reduced compared with the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α and SCGF-1β correlated with one another (P  < 0.05). Conclusion Many patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α and SCGF-1β reflects the same pathology, and these may serve as surrogate markers. [ABSTRACT FROM AUTHOR]

The remodeling of vascular grafts is critical for blood vessel regeneration. However, most scaffold materials have limited cell infiltration. In this study, we designed and fabricated a scaffold that incorporates a fast-degrading polymer polydioxanone (PDO) into the microfibrous structure by means of electrospinning technology. Blending PDO with base polymer decreases the density of electrospun microfibers yet did not compromise the mechanical and structural properties of the scaffold, and effectively enhanced cell infiltration. We then used this technique to fabricate a tubular scaffold with heparin conjugated to the surface to suppress thrombosis, and the construct was implanted into the carotid artery as a vascular graft in animal studies. This graft significantly promoted cell infiltration, and the biochemical cues such as immobilized stromal cell-derived factor-1α further enhanced cell recruitment and the long-term patency of the grafts. This work provides an approach to optimize the microfeatures of vascular grafts, and will have broad applications in scaffold design and fabrication for regenerative engineering.

Objective: The objective of this study was to investigate the use of the nanocapsule sequential delivery of BMP-2 and SDF-1α through the peripheral circulatory system to promote the healing of osteoporotic fractures. Methods: Based on increased vascular permeability in the early hematoma environment around the fracture and the presence of a large number of matrix metalloproteinase MMPs in the inflammatory environment, we designed MMP-sensitive nanocapsules which were formed viain situ free-radical polymerization on the surface of grow factors with 2-(methacryloyloxy) ethyl phosphorylcholine (MPC) and the bisacryloylated VPLGVRTK peptide. The antiphagic effect and biological activity of the growth factors for the nanomicrocapsule delivery system were tested by cell experiments. The 36 SD rats with an osteoporotic fracture model were randomly divided into six groups (A, B, C, D, E, and F). In this paper, the nanocapsules loaded with BMP-2 and SDF-1 are represented as n (BMP-2) and n (SDF-1α). In the six groups, the following different combinations of growth factors were injected into the bone defect site on days 1 and 3 after bone defect surgery: in group A, n (SDF-1α) combined with n (SDF-1α); in group B, n (BMP-2) combined with n (BMP-2); in group C, n (SDF-1α) + n (BMP-2) combined with n (SDF-1α) + n (BMP-2); in group D, n (SDF-1α) combined with n (BMP-2); in group E, n (BMP-2) combined with n (SDF-1α); in group F, nanocapsules without growth factor were used as the control group. Micro-CT was used to observe the effect of n(BMP-2) and n(SDF-1α) sequential delivery inearly healing in osteoporotic fractures. Finally, in this study, we evaluated the safety of the nanocapsules delivery system by detecting ectopic osteogenesis and inflammatory responses in animals. Results: Nanocapsules have low toxicity and protect the integrity and biological activity of growth factors. The results confirmed that nanocapsules could still be effectively targeted to the fracture site on days 1, 3, and 7 after intravenous administration. Growth factors encapsulated in nanocapsules have better bone repair results than natural growth factors. In particular, groups C and D had the best bone repair results than other groups.In vivo experiments confirmed that nanocapsules did not cause significant ectopic osteogenesis and inflammation. Conclusion: The results confirmed that the special vascular permeability and inflammatory factor microenvironment of the fracture site could be used to deliver two growth factors with a synergistic effect through venous circulation, which could better promote the healing process of osteoporotic fracture. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of naringin combined with Ad-SDF-1α on the osteogenic differentiation and migration of mesenchymal stem cells (MSC)under extremely hypoxic environment. Methods Percoll density gradi‐ ent centrifugation was used to isolate and extract rabbit MSC, which were routinely cultured and passaged. Different con‐ centrations of naringin were added to MSC and were cultured under normoxic condition for 3 days to screen the optimal ex‐ perimental concentration of naringin. MSCs of the third passage were randomly divided into five groups. The cells in the Ad-GFP group were transfected with negative control adenovirus Ad-GFP, the cells in the Ad-SDF-1α group and the naringin +Ad-SDF-1α group were transfected with Ad-SDF-1α, and the cells in the blank group and naringin group were added with blank MSCM medium and were cultured for 6 h in the normoxic environment. Cells in the naringin group and naringin + Ad-SDF-1α group were added with 1×10-4 mol/L naringin medium, and cells in the blank group, negative control Ad-GFP group, and Ad-SDF-1α group were added with blank MSCM medium. Cells in each group were cultured under extreme hypoxia for 3 days. The expression levels of osteogenic genes (BMP-2, Smad1, Smad5, Smad8, Runx2, and Osterix)and migration genes (CXCR4)were detected by qPCR. The protein expression levels of BMP-2, Smads, Runx2, Osterix, and CXCR4 were detected by Western blotting. The SDF-1α in the supernatant was detected by ELISA, the osteogenic ability of the cells was detected by alizarin red S staining, and the cell migration ability was detected by Transwell assay. Re⁃ sults The expression of BMP-2 mRNA in MSC treated with different concentrations of naringin was higher than that of 0 mol/L (all P<0. 05). The higher the concentration of naringin, the higher the expression of BMP-2. When the concen‐ tration of naringin was higher than 1×10-4 mol/L, the expression of SDF-1α and CXCR4 mRNA decreased (both P<0. 05). When the concentration of naringin was lower than 1×10-4 mol/L, there was no significant difference in SDF-1α and CXCR4 mRNA expression in comparison with that of 0 mol/L (all P>0. 05). Therefore, 1×10-4 mol/L was selected as the optimal experimental concentration of naringin. Compared with the blank group, negative control Ad-GFP group, and nar‐ ingin group, the mRNA expression levels of osteogenic genes (BMP-2, Smad1, Smad5, Smad8, Runx2, and Osterix)and migration gene (CXCR4)increased in the naringin +Ad-SDF-1α group (all P<0. 05). Compared with the blank group and the negative control Ad-GFP group, the protein expression levels of BMP-2, Smads, Runx2 and Osterix in the naringin group increased (all P<0. 05). Compared with the naringin group, the protein expression levels of BMP-2, Smads, Runx2, Osterix, SDF1-α and CXCR4 increased in the naringin +Ad-SDF-1α group, and the differences were statistically significant (all P<0. 05). Compared with the blank group, negative control Ad-GFP group, and Ad-SDF-1α group, the optical density values of calcium salt deposition in mineralized nodules were higher in the naringin group and naringin +AdSDF-1α group (all P<0. 05). Compared with the blank group, negative control Ad-GFP group, and naringin group, the absorbance values of migratory cells in Ad-SDF-1α group and naringin +Ad-SDF-1α group were higher (all P<0. 05). Conclusion Naringin and Ad-SDF-1α can synergistically promote the osteogenic differentiation of MSC under extreme hypoxia without affecting the migration ability of MSC. [ABSTRACT FROM AUTHOR]

Remote Ischemic Postconditioning (RIPostC) has become a research hotspot due to its protective effect on the brain in clinical studies related to ischemic stroke. The purpose of this study is to investigate the protective effect of RIPostC after ischemic stroke in rats. The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by the wire embolization method. RIPostC was obtained by inducing temporary ischemia in the hind limbs of rats. First, based on the results of short-term behavioral measures and long-term neurological function experiments, RIPostC was found to have a protective effect on the MCAO/R model and to improve neurological recovery in rats. Compared to the sham group, RIPostC upregulated the expression levels of C-X-C motif chemokine receptor 4(CXCR4) in the brain and stromal cell-derived factor-1(SDF-1α) in peripheral blood. In addition, RIPostC upregulated CXCR4 expression on CD34 + stem cells in peripheral blood in flow cytometric assays. Meanwhile, according to the results of EdU/DCX co-staining and CD31 staining, it was found that the effect of RIPostC on ameliorating brain injury via SDF-1α/CXCR4 signaling axis may be associated with vascular neogenesis. Finally, after inhibiting the SDF-1α/CXCR4 signaling axis using AMD3100(Plerixafor), we found that the neuroprotective effect of RIPostC was diminished. Taken together, RIPostC can improve neurobehavioral damage induced by MCAO/R in rats, and its mechanism may be related to SDF-1α/CXCR4 signaling axis. Therefore, RIPostC can be used as an intervention strategy for stroke. SDF-1α/CXCR4 signaling axis can also be a potential target for intervention. • RIPostC ameliorates ischemic stroke injury in rats. • SDF-1α/CXCR4 levels were upregulated after RIPostC in post-stroke rats. • RIPostC improved neurogenesis and angiogenesis in rats after ischemic stroke. • Inhibiting of SDF-1α/CXCR4 signaling axis could reverse the protection effects of RIPostC after stroke in rats. [ABSTRACT FROM AUTHOR]

Recruiting endogenous stem cells to deliver signaling molecules is an attractive therapeutic strategy for the treatment of skin injuries. Although various signaling molecule delivery techniques have been developed, they are limited in their ability to accurately mimic the natural physiological process in which stem cells are recruited via signaling molecule concentration gradients. Hence, herein, we developed an approach to generate persistent signaling molecule concentration gradients in microscale gel arrays. Signaling molecule concentration gradients were established in each microscale gel via chemical conjugation and were maintained for >12 days. Moreover, the microscale gel provided a suitable environment for bone mesenchymal stem cells (BMSCs) growth, with many BMSCs migrating toward the stromal cell-derived factor-1 alpha (SDF-1α) gradient in vitro. Subsequently, a patch was formulated by mounting a microscale gel array on an adhesive layer and designated as the SDF-1α gradient microscale gel array patch. In a murine full-thickness skin defect model, this patch effectively increased the recruitment of endogenous BMSCs, accelerated wound healing, and enhanced neovascularization. Moreover, the regenerated tissue was more similar to normal skin tissue, as evidenced by histological analysis. The SDF-1α gradient microscale gel array patch also proved its efficacy in a diabetic animal model. Taken together, our findings indicate that the microscale gel array system developed in this study provides an innovative strategy for accelerating wound healing by creating well-defined and localized SDF-1α gradients in vivo. Furthermore, the patch-like design will facilitate on-demand use, thereby further aiding with wound healing. The ease of use and capacity to provide long-lasting gradient signals to recruit endogenous stem cells, makes the developed patch a noninvasive, therapeutic strategy for skin regeneration after injury. [Display omitted] [ABSTRACT FROM AUTHOR]

Skin tissue engineering has progressed from simple wound dressings to biocompatible materials with desired physico-chemical properties that can deliver regenerative biomolecules. This study describes using a novel biomimetic hybrid scaffold of decellularized dermis/collagen fibers that can continuously deliver stromal cell-derived factor-1 alpha (SDF-1α) for skin regeneration. In diabetic rat models, the idea that sustained SDF-1α infusion could increase the recruitment of CXCR4-positive cells at the injury site and improve wound regeneration was investigated. The morphology of the scaffold, its biocompatibility, and the kinetics of SDF-1 release were all assessed. SDF-1α was successfully incorporated into collagen nanofibers, resulting in a 200-h continuous release profile. The microscopic observations exhibited that cells are attached and proliferated on proposed scaffolds. As evaluated by in vivo study and histological examination, fabricated scaffold with SDF-1α release capacity exhibited a remarkably more robust ability to accelerate wound regeneration than the control group. Besides, the SDF-1α-loaded scaffold demonstrated functional effects on the proliferation and recruitment of CD31 and CXCR4-positive cells in the wound bed. Additionally, no adverse effects such as hyperplasia or scarring were found during the treatment period. It may be concluded that the fabricated hybrid scaffold based on natural polymer opens up a new option for topical administration of bioactive molecules. We believe the SDF-1α-loaded hybrid scaffold has promise for skin tissue engineering. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs), one of the main members of stromal cells in tumor microenvironment are proposed to play a central role in promoting tumor metastasis. It is unclear whether and how CAFs mediates tumor metastasis or chemoresistance in human ovarian cancer. Methods: CAFs were extracted from human ovarian cancer tissues (OCs) of patients with different kinds of histological types. Results: We found that CAFs showed more aggressive potency than those tumor cells, both of which were isolated from the same ovarian cancer specimen. Moreover, when co-cultured with CAFs, cell migration abilities of ovarian cancer cells (SKOV3, OVCAR3 and HEY) were significantly increased. Next, we preliminarily detected a higher CAFs density in sections of metastatic lesions than those in primary tumor site of primary OCs clinically. However, no significant difference of stromal derived factors-1α (SDF-1α) production from CAFs was found between primary and metastatic lesions. Additionally, in contrast with tumor cells, CAFs exhibited obvious apoptosis resistance when treated with cisplatin. Furthermore, we found that cisplatin-induced cytotoxicity and apoptosis were significantly inhibited by co-cultured with recombinant human SDF-1α in SKOV3 in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. Conclusions: CAFs might be involved in the malignant metastasis in human ovarian cancer through promoting cell migration in tumor cells. And their resistance to cytotoxic agents might be mediated by paracrine SDF-1α/CXCR4 signaling in ovarian cancer. [ABSTRACT FROM AUTHOR]

Here, we developed a stromal cell-derived factor-1a (SDF-1α) delivery biomaterial as an artificial polymeric-based niche with the ability to recruit local endogenous human gingival mesenchymal stem cells (hGMSCs) for craniofacial bone regeneration applications. Polydopamine-coated poly(ε-caprolactone) (PCL)-gelatin electrospun membranes were loaded with stromal cell-derived factor-1α (SDF-1α) via physical adsorption. Subsequently, the release profile of SDF-1α and the chemotactic capacity on human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs were evaluated. The osteogenic differentiation capacity of the recruited MSCs was also assessed in vitro. Our results confirmed the sustainable release of SDF-1α from the developed biomaterial promoting the migration and homing of human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs. Moreover, the results of the osteogenic differentiation assay showed that SDF-1α delivery significantly enhanced osteogenic differentiation of hBMMSCs and hGMSCs and up-regulated the gene expression of osteogenic markers compared to the control group. In conclusion, the current study successfully developed a novel and effective treatment modality for craniofacial bone regeneration by recruiting the autogenous progenitor cells including hGMSCs. The developed niches can potentially lead to the development of a novel platform for targeted manipulation of in vivo microenvironment to achieve efficient and safe craniofacial cell reprogramming, which also will pave the road to determine the capacity of local hGMSCs' contribution to in situ bone regeneration.

The incidence of chronic diabetic wounds is increasing with the growing number of diabetic patients, and conventional wound dressings have proven to be ineffective in treating them. To address this challenge, researchers have developed artificial dermal substitutes using collagen and hyaluronic acid, which are crucial extracellular matrices. However, these subsitiues lack precision and targeted treatment. To overcome this limitation, a gene liposome nanocomplex-loaded dermal substitute (GDS) has been developed as a potential solution. This innovative biomaterial combines the benefits of liposome nanocomplexes with dermal substitutes to offer a more accurate and effective treatment option for chronic diabetic wounds. The GDS has the ability to deliver genes and therapeutic agents specifically to the wound site, promoting angiogenesis and accelerating the wound healing process. Overall, the GDS presents a promising new approach for the clinical treatment of chronic diabetic wounds, offering a targeted and effective solution for this growing problem.

Background: Stromal cell-derived factor-1α (SDF-1α) is a chemokine associated with tumor progression in various types of cancers. The current study aimed to evaluate whether pre-treatment or kinetics of SDF-1α can predict the prognosis in patients with esophageal squamous cell carcinoma (ESCC) receiving definitive concurrent chemoradiotherapy (CCRT). Methods: A total of 97 patients with ESCC were identified at Kaohsiung Chang Gung Memorial Hospital between January 2010 and December 2015. Serum concentration of SDF-1α was measured at day 0 (pre-treatment) and chemotherapy day 28 to determine its kinetics and the cut-off level of pre-chemotherapy SDF-1α was 1.5 ng/mL. Two ESCC cell lines, TE1 and KYSE30, were selected to evaluate the function of SDF-1α. Results: Univariate and multivariate analyses showed that pre-treatment SDF-1α ≥ 1.5 ng/mL and an increased SDF-1α level after treatment were significantly associated with worse progression-free survival (p = 0.021 and p = 0.008, respectively) and overall survival (p = 0.005 and p

Ischemic heart disease (IHD) is one of the main focuses in today's healthcare due to its implications and complications, and it is predicted to be increasing in prevalence due to the ageing population. Although the conventional pharmacological and interventional methods for the treatment of IHD presents with success in the clinical setting, the long-term complications of cardiac insufficiency are on a continual incline as a result of post-infarction remodeling of the cardiac tissue. The migration and involvement of stem cells to the cardiac muscle, followed by differentiation into cardiac myocytes, has been proven to be the natural process, though at a slow rate. SDF-1α is a novel candidate to mobilize stem cells homing to the ischemic heart. Endogenous SDF-1α levels are elevated after myocardial infarction, but their presence gradually decreases after approximately seven days. Additional administration of SDF-1α-releasing microspheres could be a tool for the extension of the time the stem cells are in the cardiac tissue after myocardial infarction. This, in turn, could constitute a novel therapy for more efficient regeneration of the heart muscle after injury. Through this practical study, it has been shown that the controlled release of SDF-1α from biodegradable microspheres into the pericardial sac fourteen days after myocardial infarction increases the concentration of exogenous SDF-1α, which persists in the tissue much longer than the level of endogenous SDF-1α. In addition, administration of SDF-1α-releasing microspheres increased the expression of the factors potentially involved in the involvement and retention of myocardial stem cells, which constitutes vascular endothelial growth factor A (VEGFA), stem cell factor (SCF), and vascular cell adhesion molecules (VCAMs) at the site of damaged tissue. This exhibits the possibility of combating the basic limitations of cell therapy, including ineffective stem cell implantation and the ability to induce the migration of endogenous stem cells to the ischemic cardiac tissue and promote heart repair. [ABSTRACT FROM AUTHOR]

SDF-1α, the most common isoform of stromal cell-derived factor 1, has shown vital effects in regulating chondrocyte proliferation, maturation, and chondrogenesis. Autophagy is a highly conserved biological process to help chondrocytes survive in harsh environments. However, the effect of SDF-1α on chondrocyte autophagy is still unknown. This study aims to investigate the effect of SDF-1α on chondrocyte autophagy and the underlying biomechanism. Transmission electron microscope assays and mRFP-GFP-LC3 adenovirus double label transfection assays were performed to detect the autophagic flux of chondrocytes. Western blots and immunofluorescence staining assays were used to detect the expression of autophagy-related proteins in chondrocytes. RNA sequencing and qPCR were conducted to assess changes in autophagy-related mRNA expression. SDF-1α upregulated the number of autophagosomes and autolysosomes in chondrocytes. It also increased the expression of autophagy-related proteins including ULK-1, Beclin-1 and LC3B, and decreased the expression of p62, an autophagy substrate protein. SDF-1α-mediated autophagy of chondrocytes required the participation of receptor CXCR4. Moreover, SDF-1α-enhanced autophagy of chondrocytes was through the inhibition of phosphorylation of mTOR signaling on the upstream of autophagy. Knockdown by siRNA and inhibition by signaling inhibitor further confirmed the importance of the CXCR4/mTOR signaling axis in SDF-1α-induced autophagy of chondrocytes. For the first time, this study elucidated that SDF-1α promotes chondrocyte autophagy through the CXCR4/mTOR signaling axis. [ABSTRACT FROM AUTHOR]

Stem cell treatment is a promising method of therapy for the group of patients whose conventional options for treatment have been limited or rejected. Stem cells have the potential to repair, replace, restore and regenerate cells. Moreover, their proliferation level is high. Owing to these features, they can be used in the treatment of numerous diseases, such as cancer, lung diseases or ischemic heart diseases. In recent years, stem cell therapy has greatly developed, shedding light on stromal-derived factor 1α (SDF-1α). SDF-1α is a mobilizing chemokine for application of endogenous stem cells to injury sites. Unfortunately, SDF-1α presented short-term results in stem cell treatment trials. Considering the tremendous benefits of this therapy, we developed biodegradable polymeric microspheres for the release of SDF-1α in a controlled and long-lasting manner. The microspheres were designed from poly(L-lactide/glycolide/trimethylene carbonate) (PLA/GA/TMC). The effect of controlled release of SDF-1α from microspheres was investigated on the migration level of bone marrow Mesenchymal Stromal Cells (bmMSCs) derived from a pig. The study showed that SDF-1α, released from the microspheres, is more efficient at attracting bmMSCs than SDF-1α alone. This may enable the controlled delivery of selected and labeled MSCs to the destination in the future. [ABSTRACT FROM AUTHOR]

Objective: Melittin is one of the natural components of bee venom (Apis mellifera), and its anticancer and antimetastatic properties have been well established, but the underlying mechanism remains elusive. The MDA-MB-231 is a triplenegative cell line that is highly aggressive and invasive. Besides, many critical proteins are involved in tumor invasion and metastasis. In this study, we investigated whether melittin inhibits the migration and metastasis of epidermal growth factor (EGF)-induced MDA-MB-231 cells via the suppression of SDF-1α/CXCR4 and Rac1-mediated signaling pathways. Materials and Methods: In this experimental study, cells were treated with melittin (0.5-4 μg/ml), and the toxicity of melittin was assessed by the MTT assay. Afterward, the migration assay was conducted to measure the degree of the migration of EGF-induced cells. The western blot technique was performed to analyze the rate of Rac1, p-Rac1, SDF- 1α, and CXCR4 expression in different groups. Results: The results demonstrated that melittin markedly suppressed the migration of EGF-induced cells and decreased the expression of p-Rac1, CXCR4, and SDF-1α proteins. Conclusion: The results of the present study suggested that the anti-tumor properties of melittin could be through the blocking of the SDF-1α/CXCR4 signaling pathway, which is beneficial for the reduction of tumor migration and invasion.

Background: Accumulating evidence proves that cisplatin, a widely used anticancer, causes acute kidney injury (AKI). Sitagliptin (Sita), a dipeptidyl peptidase-4 (DPP4) inhibitor, is a hypoglycemic agent that can promote tissue angiogenesis and cell survival. However, little is known about the nephroprotective effect of Sita in cisplatin-induced AKI especially its effect on SDF-1α, usually degraded by DPP4. Meanwhile, the olive oil component oleuropein (Ole) activates Nrf2/heme oxygenase-1 (HO-1) axis, which ultimately leads to SDF-1α activation. Herein, we studied the nephroprotective effects of combined Sita and Ole on oxidative stress and autophagy through SDF-1α/Nrf2/ HO-1 axis in cisplatin-induced AKI in rats. Methods: AKI was induced in vivo through single IP injection of cisplatin (7 mg/kg), while Sita (10 mg/kg) and Ole (16 mg/kg) were given separately and in combination for 7 days prior and 5 days after cisplatin injection. AKI was assessed through histopathological examination, measurement of serum creatinine and urea. Also, serum GLP-1, serum and kidney SDF-1α levels were measured by ELISA. LC3-II, P62, HO-1, Nrf2, and caspase-3 were investigated by western blotting. Results: Sita and Ole monotherapy and in combination accelerated kidney recovery as they suppress serum SDF-1α, serum BUN, creatinine and renal histopathological features. Each of Sita and Ole enhanced Nrf2/HO-1axis in renal tissues while only Sita enhanced renal SDF-1α. Sita and Ole monotherapy showed incompetent autophagy where the late steps of autophagy were incomplete. Combined treatment enhanced SDF-1α in kidney tissue which showed recovery through autophagy process. Conclusion: Sita and Ole show promising nephroprotective effects in cisplatin-induced AKI

Objective: The objective of this study was to investigate the use of the nanocapsule sequential delivery of BMP-2 and SDF-1α through the peripheral circulatory system to promote the healing of osteoporotic fractures. Methods: Based on increased vascular permeability in the early hematoma environment around the fracture and the presence of a large number of matrix metalloproteinase MMPs in the inflammatory environment, we designed MMP-sensitive nanocapsules which were formed viain situ free-radical polymerization on the surface of grow factors with 2-(methacryloyloxy) ethyl phosphorylcholine (MPC) and the bisacryloylated VPLGVRTK peptide. The antiphagic effect and biological activity of the growth factors for the nanomicrocapsule delivery system were tested by cell experiments. The 36 SD rats with an osteoporotic fracture model were randomly divided into six groups (A, B, C, D, E, and F). In this paper, the nanocapsules loaded with BMP-2 and SDF-1 are represented as n (BMP-2) and n (SDF-1α). In the six groups, the following different combinations of growth factors were injected into the bone defect site on days 1 and 3 after bone defect surgery: in group A, n (SDF-1α) combined with n (SDF-1α); in group B, n (BMP-2) combined with n (BMP-2); in group C, n (SDF-1α) + n (BMP-2) combined with n (SDF-1α) + n (BMP-2); in group D, n (SDF-1α) combined with n (BMP-2); in group E, n (BMP-2) combined with n (SDF-1α); in group F, nanocapsules without growth factor were used as the control group. Micro-CT was used to observe the effect of n(BMP-2) and n(SDF-1α) sequential delivery inearly healing in osteoporotic fractures. Finally, in this study, we evaluated the safety of the nanocapsules delivery system by detecting ectopic osteogenesis and inflammatory responses in animals. Results: Nanocapsules have low toxicity and protect the integrity and biological activity of growth factors. The results confirmed that nanocapsules could still be effectively targeted to the fracture site on days 1, 3, and 7 after intravenous administration. Growth factors encapsulated in nanocapsules have better bone repair results than natural growth factors. In particular, groups C and D had the best bone repair results than other groups.In vivo experiments confirmed that nanocapsules did not cause significant ectopic osteogenesis and inflammation. Conclusion: The results confirmed that the special vascular permeability and inflammatory factor microenvironment of the fracture site could be used to deliver two growth factors with a synergistic effect through venous circulation, which could better promote the healing process of osteoporotic fracture.

Background: The present research has been undertaken to study the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of neuroinflammation-induced cognitive disorders. Methods: Either umbilical cord or adipose MSCs were injected into mice treated with lipopolysaccharide. The mice were studied in behavioral tests, and their brains were examined by means of immunohistochemistry, electron microscopy and sandwich ELISA. Results: MSCs, introduced either intravenously or intraperitoneally, restored episodic memory of mice disturbed by inflammation, normalized nAChR and Aβ1–42 levels and stimulated proliferation of neural progenitor cells in the brain. The effect of MSCs was observed for months, whereas that of MSC-conditioned medium was transient and stimulated an immune reaction. SDF-1α potentiated the effects of MSCs on the brain and memory. Conclusion: MSCs of different origins provide a long-term therapeutic effect in the treatment of neuroinflammation-induced episodic memory impairment. [ABSTRACT FROM AUTHOR]

Abstract Aims Neointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown. Methods and results Aneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42. Conclusions Spatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4.

Background: Mesenchymal Stem Cells (MSCs) therapy has become a new coming focus of clinical research in regenerative medicine. However, only a small number of implanted MSCs could successfully reach the injured areas. The previous studies have shown that fracture healing time is inversely proportional to concentration of MSCs in injured tissue. Methods: The migration and osteogenesis of MSCs were assessed by transwell assay and Alizarin Red S staining. Levels of gene and protein expression were checked by qPCR and Western Blot. On the other hand, the enhanced migration ability of MSCs induced by Cyasterone was retarded by CXCR4 siRNA. In addition, the rat model of femoral fracture was established to evaluate the effect of Cyasterone on fracture healing. What's more, we also checked the effect of Cyasterone on mobilisation of MSCs in vivo. Results: The results showed that Cyasteron increased the number of MSCs in peripheral blood. The concentrations of SDF-1α in serum at different time points were determined by ELISA assay. Micro-CT and histological analysis were used to evaluate the fractured femurs.Our results showed that Cyasterone could promote the migration and osteogenesis capacities of MSCs. The fractured femurs healed faster with treatment of Cyasterone. Meanwhile, Cyasterone could significantly increase the level of SDF-1α in rats with femur fracture. Conclusion: Cyasterone could promote migration and osteogenesis of MSCs, and most importantly, it could accelerate bone fracture healing.Translational Potential statement: These findings provide evidence that Cyasterone could be used as a therapeutic reagent for MSCs mobilisation and osteogenesis. What's more, it could acclerate fracture healing.

Based on its multifactorial nature, successful treatment of diabetic wounds requires combinatorial approach. In this regard, we hypothesized that engraftment of a bioengineered micro-porous three-dimensional human amniotic membrane-scaffold (HAMS) loaded by SDF-1α (SHAMS) in combination with hyperbaric oxygen (HBO), throughout mobilization and recruitment of endothelial progenitor cells (EPCs), could accelerate wound healing in rats with type 1 diabetes mellitus. To test this hypothesis, 30 days after inducting diabetes, an ischemic wound was created in rat skin and treatments were performed for 21 days. In addition to wounded non-diabetic (ND) group, diabetic animals were randomly divided into non-treated (NT-D), HBO-treated (HBO-D), HBO-treated plus HAMS transplantation (HBO+HAMS-D) or HBO-treated in combination with SHAMS transplantation (HBO+SHAMS-D) groups. Our results on post-wounding days 7, 14 and 21 showed that the wound closure, volume of new dermis and epidermis, numerical density of basal cells of epidermis, fibroblasts and blood vessels, number of proliferating cells, deposition of collagen and biomechanical properties of healed wound were considerably higher in both HBO+HAMS-D and HBO+SHAMS-D groups in comparison to those of the NT-D and HBO-D groups, and were the highest in HBO+SHAMS-D ones. The transcripts for Vegf , bFgf , and Tgf-β genes were significantly upregulated in all treatment regimens compared to NT-D group and were the highest for HBO+SHAMS-D group. This is while expression of Tnf-α and Il-1β as well as cell density of neutrophil and macrophage decreased more significantly in HBO+SHAMS-D group as compared with NT-D or HBO-D groups. Overall, it was found that using both HAMS transplantation and HBO treatment has more impact on diabetic wound healing. Moreover, SDF-1α loading on HAMS could transiently improve the wound healing process, as compared with the HBO+HAMS-D group on day 7 only. [ABSTRACT FROM AUTHOR]

Chemokines, such as stromal cell-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF), are associated with clinical outcomes in several cancer types. This study aimed to investigate the role of SDF-1α and VEGF in the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) who underwent TPF induction chemotherapy (docetaxel, cisplatin, and 5-fluorouracil). A total of 77 HNSCC patients were enrolled and circulating SDF-1α and VEGF values were examined at two time points for each patient, including pre-TPF treatment (treatment-naïve) and post-TPF treatment but before chemoradiotherapy. The median progression-free survival (PFS) and overall survival (OS) were 18.1 and 32.9 months, respectively. Decreased SDF-1α and VEGF levels after TPF treatment, post-TPF SDF-1α < 1500 pg/mL and VEGF value < 150 pg/mL were independent prognostic factors for better PFS and OS in univariate and multivariate analyses. A combination of SDF-1α and VEGF values may predict clinical outcomes significantly. Our study confirmed the role of SDF-1α and VEGF in the disease progression of HNSCC, and that decreased SDF-1α and VEGF after TPF treatment and lower post-TPF SDF-1α and VEGF values were associated with better prognosis in HNSCC patients who received induction chemotherapy with TPF followed by chemoradiotherapy. [ABSTRACT FROM AUTHOR]

AbstractIntroduction The inflammatory hypothesis of atherosclerosis is appealing in acute coronary syndromes, but the dynamics and precise role are not established.Objectives The study investigates the levels of C reactive protein (CRP), interleukin 1β (IL-1β) and stromal-derived factor 1α (SDF-1α) at the time of acute myocardial infarction (AMI) and at 1 and 6 months afterwards, compared with a control group.Results In the acute phase of AMI, CRP and SDF-1α were significantly higher, while IL-1β showed lower levels compared with controls. CRP positively correlated with coronary stenosis severity (rho = 0.3, p=.05) and negatively related with left ventricle ejection fraction (LVEF) at 1 month (rho= −0.43, p=.05). IL-1β weakly correlated with the severity of coronary lesions (rho =0.29, p=.02) and strongly with LVEF (rho= −0.8, p=.05). SDF-1α, slightly correlated with LVEF at 1 month (rho = 0.22, p=.01) and with the severity of coronary atherosclerosis (rho= −0.41, p=.003).Conclusions CRP, IL-1β and SDF-1α have important dynamic in the first 6 months after AMI and CRP and SDF-1α levels correlated with the severity of coronary lesions and LVEF at 1 month after the acute ischaemic event.

Objective: Melittin is one of the natural components of bee venom (Apis mellifera), and its anticancer and antimetastatic properties have been well established, but the underlying mechanism remains elusive. The MDA-MB-231 is a triplenegative cell line that is highly aggressive and invasive. Besides, many critical proteins are involved in tumor invasion and metastasis. In this study, we investigated whether melittin inhibits the migration and metastasis of epidermal growth factor (EGF)-induced MDA-MB-231 cells via the suppression of SDF-1α/CXCR4 and Rac1-mediated signaling pathways. Materials and Methods: In this experimental study, cells were treated with melittin (0.5-4 μg/ml), and the toxicity of melittin was assessed by the MTT assay. Afterward, the migration assay was conducted to measure the degree of the migration of EGF-induced cells. The western blot technique was performed to analyze the rate of Rac1, p-Rac1, SDF- 1α, and CXCR4 expression in different groups. Results: The results demonstrated that melittin markedly suppressed the migration of EGF-induced cells and decreased the expression of p-Rac1, CXCR4, and SDF-1α proteins. Conclusion: The results of the present study suggested that the anti-tumor properties of melittin could be through the blocking of the SDF-1α/CXCR4 signaling pathway, which is beneficial for the reduction of tumor migration and invasion. [ABSTRACT FROM AUTHOR]

The inflammatory hypothesis of atherosclerosis is appealing in acute coronary syndromes, but the dynamics and precise role are not established. The study investigates the levels of C reactive protein (CRP), interleukin 1β (IL-1β) and stromal-derived factor 1α (SDF-1α) at the time of acute myocardial infarction (AMI) and at 1 and 6 months afterwards, compared with a control group. In the acute phase of AMI, CRP and SDF-1α were significantly higher, while IL-1β showed lower levels compared with controls. CRP positively correlated with coronary stenosis severity (rho = 0.3, p=.05) and negatively related with left ventricle ejection fraction (LVEF) at 1 month (rho= −0.43, p=.05). IL-1β weakly correlated with the severity of coronary lesions (rho =0.29, p=.02) and strongly with LVEF (rho= −0.8, p=.05). SDF-1α, slightly correlated with LVEF at 1 month (rho = 0.22, p=.01) and with the severity of coronary atherosclerosis (rho= −0.41, p=.003). CRP, IL-1β and SDF-1α have important dynamic in the first 6 months after AMI and CRP and SDF-1α levels correlated with the severity of coronary lesions and LVEF at 1 month after the acute ischaemic event. [ABSTRACT FROM AUTHOR]

Abstract Background Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. Methods We test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos. Discussion The REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy. Trial registration EudraCT no.: 2018-000916-75 . Registered on 7 June 2018. IND number: 123717

Zinat Yazdani,1 Zahra Mousavi,2 Alireza Moradabadi,1 Gholamhossein Hassanshahi1,3 1Department of Hematology and Blood Banking, Kerman University of Medical Sciences, Kerman, Iran; 2Department of Hematology and Medical Laboratory Sciences, Iranshahr University of Medical Sciences, Iranshahr, Iran; 3Molecular Medicine Research Center, Institute of Basic Medical Sciences Research, Rafsanjan University of Medical Sciences, Rafsanjan, IranCorrespondence: Gholamhossein HassanshahiDepartment of Hematology and Blood Banking, Kerman University of Medical Sciences, Kerman, IranTel +98 391 5234 0035Fax +98 391 522 5209Email ghassanshahi@gmail.comAbstract: Acute myeloid leukemia (AML) is defined as an aggressive disorder which is described by accumulation of immature malignant cells into the bone marrow. Chemokine-receptor axes are defined as factors involved in AML pathogenesis and prognosis. The chemokine receptor CXCR4 along with its ligand, CXCL12 fit in important players that are actively involved in the cross-talk between leukemia cells and bone marrow microenvironment. Therefore, according to the above introductory comments, in this review article, we have focused on delineating some parts played by CXCL12/CXCR4 axis in various aspects of AML malignancy. Targeting both leukemic and stromal cell interaction is nowadays accepted as a wide and attractive strategy for improving the outcome of treatment in AML in a non-cell autonomous manner. This strategy might be employed in a wide variety of AML patients regardless of their causative mutations. In addition to several potential targets involved in the disruption of malignant leukemic cells from their specific protective niches, compounds which interfere with CXCL12/CXCR4 axis have also been explored in multiple early-phase established clinical trials. Moreover, extensive research programs are exploring novel leading mechanisms for leukemia-stromal interactions that appear to find out novel therapeutic targets within the near future.Keywords: SDF-1α, CXCL12, CXCR4, chemokine axis, AML

Abstract Background Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. Methods Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. Results The optimal conditions for S-GECS was determined to be 1052 GECS cells/mm2 and a 48 h culture period to produce spheroids. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl2-induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. Conclusions Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).

Ischemic heart disease (IHD) is one of the main focuses in today’s healthcare due to its implications and complications, and it is predicted to be increasing in prevalence due to the ageing population. Although the conventional pharmacological and interventional methods for the treatment of IHD presents with success in the clinical setting, the long-term complications of cardiac insufficiency are on a continual incline as a result of post-infarction remodeling of the cardiac tissue. The migration and involvement of stem cells to the cardiac muscle, followed by differentiation into cardiac myocytes, has been proven to be the natural process, though at a slow rate. SDF-1α is a novel candidate to mobilize stem cells homing to the ischemic heart. Endogenous SDF-1α levels are elevated after myocardial infarction, but their presence gradually decreases after approximately seven days. Additional administration of SDF-1α-releasing microspheres could be a tool for the extension of the time the stem cells are in the cardiac tissue after myocardial infarction. This, in turn, could constitute a novel therapy for more efficient regeneration of the heart muscle after injury. Through this practical study, it has been shown that the controlled release of SDF-1α from biodegradable microspheres into the pericardial sac fourteen days after myocardial infarction increases the concentration of exogenous SDF-1α, which persists in the tissue much longer than the level of endogenous SDF-1α. In addition, administration of SDF-1α-releasing microspheres increased the expression of the factors potentially involved in the involvement and retention of myocardial stem cells, which constitutes vascular endothelial growth factor A (VEGFA), stem cell factor (SCF), and vascular cell adhesion molecules (VCAMs) at the site of damaged tissue. This exhibits the possibility of combating the basic limitations of cell therapy, including ineffective stem cell implantation and the ability to induce the migration of endogenous stem cells to the ischemic cardiac tissue and promote heart repair.

SDF-1α, the most common isoform of stromal cell-derived factor 1, has shown vital effects in regulating chondrocyte proliferation, maturation, and chondrogenesis. Autophagy is a highly conserved biological process to help chondrocytes survive in harsh environments. However, the effect of SDF-1α on chondrocyte autophagy is still unknown. This study aims to investigate the effect of SDF-1α on chondrocyte autophagy and the underlying biomechanism. Transmission electron microscope assays and mRFP-GFP-LC3 adenovirus double label transfection assays were performed to detect the autophagic flux of chondrocytes. Western blots and immunofluorescence staining assays were used to detect the expression of autophagy-related proteins in chondrocytes. RNA sequencing and qPCR were conducted to assess changes in autophagy-related mRNA expression. SDF-1α upregulated the number of autophagosomes and autolysosomes in chondrocytes. It also increased the expression of autophagy-related proteins including ULK-1, Beclin-1 and LC3B, and decreased the expression of p62, an autophagy substrate protein. SDF-1α-mediated autophagy of chondrocytes required the participation of receptor CXCR4. Moreover, SDF-1α-enhanced autophagy of chondrocytes was through the inhibition of phosphorylation of mTOR signaling on the upstream of autophagy. Knockdown by siRNA and inhibition by signaling inhibitor further confirmed the importance of the CXCR4/mTOR signaling axis in SDF-1α-induced autophagy of chondrocytes. For the first time, this study elucidated that SDF-1α promotes chondrocyte autophagy through the CXCR4/mTOR signaling axis.

Stem cell treatment is a promising method of therapy for the group of patients whose conventional options for treatment have been limited or rejected. Stem cells have the potential to repair, replace, restore and regenerate cells. Moreover, their proliferation level is high. Owing to these features, they can be used in the treatment of numerous diseases, such as cancer, lung diseases or ischemic heart diseases. In recent years, stem cell therapy has greatly developed, shedding light on stromal-derived factor 1α (SDF-1α). SDF-1α is a mobilizing chemokine for application of endogenous stem cells to injury sites. Unfortunately, SDF-1α presented short-term results in stem cell treatment trials. Considering the tremendous benefits of this therapy, we developed biodegradable polymeric microspheres for the release of SDF-1α in a controlled and long-lasting manner. The microspheres were designed from poly(L-lactide/glycolide/trimethylene carbonate) (PLA/GA/TMC). The effect of controlled release of SDF-1α from microspheres was investigated on the migration level of bone marrow Mesenchymal Stromal Cells (bmMSCs) derived from a pig. The study showed that SDF-1α, released from the microspheres, is more efficient at attracting bmMSCs than SDF-1α alone. This may enable the controlled delivery of selected and labeled MSCs to the destination in the future.

Aims: Neointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown. Methods and results: Aneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42. Conclusions: Spatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4. [ABSTRACT FROM AUTHOR]

Rapid and functional bone‐tendon (B‐T) healing remains a difficulty in clinical practice. Tissue engineering has emerged as a promising strategy to address this problem. However, the majority of tissue engineering scaffolds are loaded with stem cells to enhance the regenerability in B‐T healing, which is complicated and inconvenient for clinical application. Accordingly, developing a cell‐free scaffold with chemotactic function and chondrogenic inducibility may be an effective approach. In this study, a collagen affinity peptide derived from the A3 domain of von Willebrand factor (a hemostasis factor) was fused into the C‐terminal of a stromal cell‐derived factor‐1α (SDF‐1α) to synthesize a recombinant SDF‐1α capable of binding collagen and chemotactic activity. The recombinant SDF‐1α was then tethered on the collagen fibers of a book‐shaped acellular fibrocartilage scaffold (BAFS), thus fabricating a novel scaffold (C‐SDF‐1α/BAFS) with chemotactic function and chondrogenic inducibility. In vitro tests determined that this scaffold was noncytotoxic and biomimetic, could attract stem cells migrating to the scaffold using sustainably released C‐SDF‐1α, and inducedthe interacting stem cells down the chondrogenic lineage. In vivo, the C‐SDF‐1α/BAFS significantly enhanced the B‐T healing in a rabbit partial patellectomy model, as shown by the larger cartilaginous metaplasia region, better fibrocartilage regeneration, additional bone formation, and improved biomechanical properties. Therefore, the findings of the study demonstrate that the C‐SDF‐1α/BAFS could potentially be applied for B‐T healing. [ABSTRACT FROM AUTHOR]

Abstract Introduction Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. Methods and results The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells’ differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA. Conclusions S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.

The leukocyte adhesion cascade is of critical importance for both the maintenance of immune homeostasis and the ability of immune cells to perform effector functions. Here, we present data showing CD4+ T cells migrate upstream (against the direction of flow) after completing the leukocyte adhesion cascade on surfaces displaying either ICAM-1 or ICAM-1 and VCAM-1, but migrate downstream on surfaces displaying only VCAM-1. Cells completing the cascade on HUVECs initially migrate upstream before reverting to more random migration, partly caused by transmigration of cells migrating against the flow. Furthermore, cells migrating upstream transmigrate faster than cells migrating downstream. On HUVECs, blocking interactions between LFA-1 and ICAM-1 resulted in downstream migration and slower transmigration. These results further suggest a possible physiological role for upstream migration in vivo.

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.

Chemokines, such as stromal cell-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF), are associated with clinical outcomes in several cancer types. This study aimed to investigate the role of SDF-1α and VEGF in the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) who underwent TPF induction chemotherapy (docetaxel, cisplatin, and 5-fluorouracil). A total of 77 HNSCC patients were enrolled and circulating SDF-1α and VEGF values were examined at two time points for each patient, including pre-TPF treatment (treatment-naïve) and post-TPF treatment but before chemoradiotherapy. The median progression-free survival (PFS) and overall survival (OS) were 18.1 and 32.9 months, respectively. Decreased SDF-1α and VEGF levels after TPF treatment, post-TPF SDF-1α < 1500 pg/mL and VEGF value < 150 pg/mL were independent prognostic factors for better PFS and OS in univariate and multivariate analyses. A combination of SDF-1α and VEGF values may predict clinical outcomes significantly. Our study confirmed the role of SDF-1α and VEGF in the disease progression of HNSCC, and that decreased SDF-1α and VEGF after TPF treatment and lower post-TPF SDF-1α and VEGF values were associated with better prognosis in HNSCC patients who received induction chemotherapy with TPF followed by chemoradiotherapy.

Enhancing angiogenesis is the prime target of current biomaterial‐based wound healing strategies. However, these approaches largely overlook the angiogenic role of the cells of the nervous system. Therefore, we explored the role of a collagen‐chondroitin sulfate scaffold functionalized with a proangiogenic gene stromal‐derived factor‐1α (SDF‐1α)—an SDF‐1α gene‐activated scaffold on the functional regulation of human Schwann cells (SCs). A preliminary 2D study was conducted by delivering plasmids encoding for the SDF‐1α gene into a monolayer of SCs using polyethyleneimine‐based nanoparticles. The delivery of the SDF‐1α gene into the SCs enhanced the production of proangiogenic vascular endothelial growth factor (VEGF). Subsequently, we investigated the impact of SDF‐1α gene‐activated scaffold (3D) on the SCs for 2 weeks, using a gene‐free scaffold as control. The transfection of the SCs within the gene‐activated scaffold resulted in transient overexpression of SDF‐1α transcripts and triggered the production of bioactive VEGF that enhanced endothelial angiogenesis. The overexpression of SDF‐1α also caused transient activation of the transcription factor c‐Jun and supported the differentiation of SCs towards a repair phenotype. This was characterized by elevated expression of neurotrophin receptor p75NGFR. During this developmental stage, the SCs also performed an extensive remodelling of the basement matrix (fibronectin, collagen IV, and laminin) to enrich their environment with the pro‐neurogenic matrix protein laminin, revealing an enhanced pro‐neurogenic behavior. Together, this study shows that SDF‐1α gene‐activated scaffold is a highly bioinstructive scaffold capable of enhancing proangiogenic regenerative response in human SCs for improved wound healing. [ABSTRACT FROM AUTHOR]