Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells en...Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.展开更多
Background Previous evidence suggests that methionine(Met)consumption can promote placental angiogenesis and improve fetal survival.To investigate the mechanisms by which increased levels of Met as hydroxyl-Met(OHMet)...Background Previous evidence suggests that methionine(Met)consumption can promote placental angiogenesis and improve fetal survival.To investigate the mechanisms by which increased levels of Met as hydroxyl-Met(OHMet)improve placental function,forty sows were divided into four groups and fed either a control diet,or diets supplemented with 0.15%OHMet,0.3%OHMet or 0.3%Met(n=10).Placentas were collected immediately after expulsion,and extracted proteins were analyzed by tandem mass tag based quantitative proteomic analysis.Results We found that 0.15%OHMet consumption significantly increased placental vascular density compared with the control.Proteomic analysis identified 5,136 proteins,87 of these were differentially expressed(P<0.05,|fold change|>1.2).Enriched pathways in the Kyoto Encyclopedia of Genes and Genomes for 0.15%OHMet vs.control and 0.15%OHMet vs.0.3%OHMet were glutathione metabolism;for 0.15%OHMet vs.0.3%Met,they were NOD-like receptor signaling and apoptosis.Further analysis revealed that 0.15%OHMet supplementation upregulated the protein expression of glutathione-S-transferase(GSTT1)in placentas and trophoblast cells compared with the control and 0.3%OHMet groups,upregulated thioredoxin(TXN)in placentas and trophoblast cells compared with the 0.3%OHMet and 0.3%Met groups,and decreased reactive oxygen species(ROS)levels in trophoblast cells compared with other groups.In contrast,sows fed 0.3%OHMet or 0.3%Met diets increased placental interleukin 1βlevels compared with the control,and upregulated the protein expression of complex I-B9(NDUFA3)compared with the 0.15%OHMet group.Furthermore,homocysteine,an intermediate in the trans-sulphuration pathway of Met,damaged placental function by inhibiting the protein expression of TXN,leading to apoptosis and ROS production.Conclusion Although dietary 0.15%OHMet supplementation improved placental angiogenesis and increased antioxidative capacity,0.3%OHMet or 0.3%Met supplementation impaired placental function by aggravating inflammation and oxidative stress,which is associated with cumulative homocysteine levels.展开更多
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose a...Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular networks.Brain vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the brain.This elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing vasculature.Brain capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.展开更多
Exosomes(EXOs)play an important role in the progression of breast cancer.EXOs,with a diameter of approximately 100 nm,have a simple structure but diverse functions,and can affect the development of breast cancer throu...Exosomes(EXOs)play an important role in the progression of breast cancer.EXOs,with a diameter of approximately 100 nm,have a simple structure but diverse functions,and can affect the development of breast cancer through signal transduction and molecular transfer,etc.Angiogenesis provides nutrients for the growth and metastasis of breast cancer and is a crucial part of tumor progression.The mechanism of tumor angiogenesis is complex.The VEGF/VEGFR pathway promotes angiogenesis by regulating the activities of ECs.Hypoxia,a common feature in the tumor microenvironment,as a key regulator,can affect angiogenesis in multiple aspects such as the transfer of miRNAs in EXOs,protein transport,extracellular matrix regulation,and metabolic adaptation.The Notch pathway has a bidirectional regulatory role in breast cancer angiogenesis,and different molecules can promote or inhibit angiogenesis.EXOs secreted by breast cancer cells are rich in angiogenic factors.Components such as proteins and nucleic acids in EXOs can affect the functions and behaviors of vascular ECs,thereby influencing breast cancer angiogenesis.Research on the mechanisms of EXOs in breast cancer angiogenesis is of great significance for tumor treatment.EXOs are expected to become biomarkers for breast cancer diagnosis/prognosis.This research provides potential targets for in-depth understanding of the biological characteristics of breast cancer and the development of new treatment strategies.展开更多
Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temp...Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.展开更多
Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and mol...Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and molecular changes remain unclear.This study investigated platelet-derived growth factor receptor beta-positive(Pdgfrb+)pericyte dynamics and reprogramming in GBM vasculature.Methods:We generated GL261-Luc and GL261-CFP glioblastoma cells via lentiviral transduction and established two transgenic models.(1)For pericyte labeling,Ai14 reporter mice was crossed with PDGFRβ-P2A-CreERT2mice for td Tomato-specific lineage tracing(PT mice).(2)For conditional ablation,we generated inducible Pdgfrb-expressing cell ablation models(PT mice was crossed with ROSA-DTA mice).An intravital imaging platform(FITC-dextran/CFP/td Tomato+two-photon microscopy)tracked pericytes,vessels,and tumor cells,while FACSsorted Pdgfrb+cells from GBM and normal brain were analyzed by LC-MS/MS proteomics.Results:Cre-mediated ablation of Pdgfrb-expressing cells revealed stage-dependent effects on GBM growth:early ablation inhibited progression while late ablation promoted it.Pericytes undergo dual spatial reorganization in GBM:regional enrichment with pre-sprouting accumulation at the tumor-brain interface,and focal positioning with preferential localization at vascular branch points.Concurrently,GBM vasculature displayed simplified branching,dilation,and pericyte remodeling(shorter processes,higher density).Proteomics revealed 1426 altered proteins,with upregulated proliferation pathways(e.g.,matrix metallopeptidase 14[Mmp14],lysyl oxidase like 2[Loxl2])and downregulated homeostasis functions(e.g.,transforming growth factor beta 1[Tgfb1]),validated by scRNA-seq in human GBM.Conclusions:This study demonstrates that during early GBM progression,pericytes actively drive tumor angiogenesis through molecular reprogramming toward proliferative and pro-angiogenic phenotypes,with the integrated imaging-proteomics framework revealing potential therapeutic targets for disrupting pericyte-mediated vascular remodeling.展开更多
Background Embryo implantation in early gestation is crucial for reproductive success,while dietary fiber plays a key role in regulating sow fertility.However,the underlying mechanisms remain unclear.This study explor...Background Embryo implantation in early gestation is crucial for reproductive success,while dietary fiber plays a key role in regulating sow fertility.However,the underlying mechanisms remain unclear.This study explores the influence of dietary inulin on embryonic implantation using a sow model.Sows were fed a diet supplemented with 11 g/kg of inulin during early gestation and were slaughtered on gestation day 19(G19).Uterine fluid exosomes(UFEs)and endometrial tissues were collected for high-throughput sequencing and for analysis of the expression of angiogenesis-related genes and proteins,respectively.Furthermore,UFEs obtained from slaughtered sows were injected into G19 sows to investigate the effects on reproduction and angiogenesis.Results The results showed that inulin significantly increased the number of blood vessels in the endometrium and expression of the angiogenesis-related proteins MMP2 and ANGPT1 in G19 sows(P<0.05).Bioinformatics analysis revealed that inulin significantly downregulated miRNAs associated with angiogenesis inhibition in UFEs,while upregulating miRNAs related to trophoblast physiological activities and regulation of the uterine fluid microenvironment(P<0.05).Furthermore,intravenous injection of G19 sows with UFEs from sows fed a diet containing inulin had significantly promoted vascular formation in the endometrium and embryos,and increased the number of live embryos on gestation day 28(G28)(P<0.05).Additionally,the mRNA expression levels of MMP2,ANGPT1,and VEGF in the placentas of sows were significantly elevated on G28 and at farrowing in the UFEs injection group(P<0.05).Conclusion Dietary supplementation with inulin during early gestation in sows promoted embryo implantation by regulating angiogenesis at the maternal–fetal interface through the modulation of miRNA expression in UFEs.These findings provide a theoretical reference for the application of dietary fiber in sow nutrition.展开更多
Pericytes are multifunctional mural cells that surround the abluminal wall of endothelial cells and are associated with vascular development,vascular permeability,and angiogenesis.Additionally,pericytes demonstrate st...Pericytes are multifunctional mural cells that surround the abluminal wall of endothelial cells and are associated with vascular development,vascular permeability,and angiogenesis.Additionally,pericytes demonstrate stem cell-like properties and contribute to neuroinflammatory processes.Pericytes have been extensively studied in the central nervous system.However,specific mechanisms underlying its involvement in various physiological and pathological conditions,especially in erectile dysfunction(ED),remain poorly understood.Advancements in in vitro and in vitro techniques,such as single-cell RNA sequencing,are expanding our understanding of pericytes.Recent studies have shown that pericyte dysfunction is considered an important factor in the pathogenesis of vascular and neurological ED.Therefore,this study aims to analyze the specific role of pericytes in ED,focusing on diabetic and neurogenic ED.This article provides a comprehensive review of research findings on PubMed from 2000 to 2023,concerning pericyte dysfunction in the process of ED,offering valuable insights,and suggesting directions for further research.展开更多
Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disorder that was clinically treated by core decompression (CD) combined with bone grafting.However,the clinical outcome of this therapy for S...Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disorder that was clinically treated by core decompression (CD) combined with bone grafting.However,the clinical outcome of this therapy for SONFH is usually unsatisfactory.Magnesium (Mg) is a biodegradable material reported as an ideal orthopedic implant.The Mg^(2+)released from its degradation is considered an effective factor for bone tissue formation,but the rapid degradation rate limited its application.Here,we reported a magnesiumDscandium (MgDSc) alloy for promoting bone regeneration in SONFH.We discovered that MgDSc alloy with satisfied corrosion resistance,antiapoptosis,angiogenic,and osteogenic properties in vitro,could facilitate osteogenic differentiation by activating the Wnt/β-catenin signaling pathway.In the clinically relevant SONFH model,CD combined with suitable MgDSc alloy implantation promoted angiogenesisDosteogenesis coupling and alleviated osteonecrosis.We observed fewer apoptotic osteocytes and empty bone lacunae,but more blood vessels and new bone formation in the Mg-Sc alloy implanted CD tunnel region compared with CD-treated SONFH rabbits.Properly degraded MgDSc alloy maintains high structural integrity and provides reliable mechanical support for the osteonecrotic femoral head,which is conducive to further clinical translation.展开更多
BACKGROUND SLC16A8,a lactate efflux transporter,is upregulated in various cancers,but its effects on tumor microenvironments remain understudied.This research explores its role in colorectal cancer(CRC)and the impact ...BACKGROUND SLC16A8,a lactate efflux transporter,is upregulated in various cancers,but its effects on tumor microenvironments remain understudied.This research explores its role in colorectal cancer(CRC)and the impact on the associated microenvir-onment consisting of vascular endothelial cells.AIM To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.METHODS Hypoxic conditions prompted examination of SLC16A8 expression,glycolysis,lactate efflux,and Warburg effect correlations in CRC cell lines.Co-culture with HUVEC allowed for endothelial-mesenchymal transition(EndMT)character-ization,revealing lactate efflux's influence.Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments,investigating tumor growth,blood vessel distribution,and signaling pathway alterations.RESULTS SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression(P<0.05).Under hypoxic conditions,HIF-1αinduced SLC16A8 expression,leading to enhanced metabolic reprogramming and increased lactate production.siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes,including reduced glucose consumption and lactate production.Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells.In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth,reduced Ki67 expression,and decreased HIF-1αlevels.Furthermore,SLC16A8 silencing led to decreased ex-pression of key metabolic enzymes PKM2 and LDHA,indicating its role in glycolytic regulation.CONCLUSION Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.展开更多
Colorectal cancer(CRC)ranks among the top five most common malignant tumors worldwide and has a high mortality rate.Angiogenesis plays an important role in CRC progression;however,anti-angiogenesis therapy still has m...Colorectal cancer(CRC)ranks among the top five most common malignant tumors worldwide and has a high mortality rate.Angiogenesis plays an important role in CRC progression;however,anti-angiogenesis therapy still has many limitations.Long non-coding RNAs(lncRNAs)participate in tumor progression by regulating the expression of vascular endothelial growth factor in metastatic CRC.Thus,targeting specific lncRNAs may provide some new hope for anti-angiogenic strategies.Through analyzing data from both clinical samples and The Cancer Genome Atlas database,we found that the lncRNA LINC01503 was specifically upregulated in CRC tissues and was associated with tumor progression and poor overall survival.We also demonstrated that LINC01503 enhanced the capacity for tube formation and migration of vascular endothelial cells,thus promoting CRC tumorigenesis by upregulating vascular endothelial growth factor A(VEGFA)expression in CRC cells.Mechanistically,LINC01503 promoted the expression of VEGFA by simultaneously regulating both mRNA and protein stability of VEGFA by binding to miR-342-3p and the chaperone HSP60,respectively.The upregulation of LINC01503 in CRC cells was attributed to the CREB-binding protein CBP/p300-mediated H3K27 acetylation of the LINC01503 promoter region.Taken together,our findings clarify the mechanism by which LINC01503 may promote CRC angiogenesis,implying that LINC01503 may serve as a potential prognostic biomarker and therapeutic target for CRC.展开更多
BACKGROUND Diabetic foot ulcers(DFU)are estimated to affect about 18.6 million people worldwide annually.The pathogenesis of DFU is complex,and the available drugs are not effective.Dl-3-n-butylphthalide(NBP)is a synt...BACKGROUND Diabetic foot ulcers(DFU)are estimated to affect about 18.6 million people worldwide annually.The pathogenesis of DFU is complex,and the available drugs are not effective.Dl-3-n-butylphthalide(NBP)is a synthetic mixture of racemates used in China for the treatment of ischemic stroke.It was initially isolated from the seeds of Apium graveolens Linn,with studies showing its potential role in treating diabetes and its complications.AIM To predict and validate the mechanism by which NBP treats DFU.METHODS Network pharmacological analysis was performed to identify pharmacological targets and signaling pathways mediating the treatment effect of NBP on DFU.In vivo and in vitro experiments were conducted to validate the therapeutic effects and mechanisms of NBP on DFU.RESULTS Network pharmacology analysis identified 26 pharmacological targets of NBP and predicted that NBP could treat DFU partially by modulating apoptosis and vascular signaling pathways.Results from animal experiments showed that NBP significantly improved DFU by increasing neovascularization and fibroblast proliferation.In vitro tests demonstrated that NBP treatment promoted the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts,while inhibiting the apoptosis of human umbilical vein endothelial cells,human dermal fibroblasts,and human keratinocytes cells.CONCLUSION This study found that NBP could treat DFU by decreasing the rate of apoptosis and increasing angiogenesis via the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to the heme oxygenase 1,caspase 3,B cell leukemia/lymphoma 2,brain derived neurotrophic factor,and nuclear factor erythroid 2 L2 genes.展开更多
BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from...BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from elderly patients in comparison to that of bone marrow-derived MSCs(BMSCs)from the same elderly patients.The metabolomics results revealed a significantly higher Larginine excretion from aged ADSCs vs BMSCs in hypoxic conditions.This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed.Then,arginine succinate lyase(ASL)overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs.Subsequently,in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control,BMSCs,BMSCs ASL short hairpin RNA,BMSCs ASL overexpressed,and BMSC negative control on cocultured human umbilical vein endothelial cells.All sample sizes,which were determined to meet the statistical requirements and be greater than 3,were established on the basis of previously established literature standards.The protein levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor,etc.were detected.In vivo,the five types of cells were transplanted into the infarcted area of MI rat models,and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.RESULTS Metabolomic analysis showed that L-arginine was increased.Using ASL gene transfection,we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro,which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression,VEGF and basic fibroblast growth factor secretion,and inductive angiogenesis to levels comparable to donor-matched ADSCs.After the cell transplantation in vivo,the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells,enhanced vessel formation,reduced scar size,and improved cardiac function in the MI rat model.The therapeutic efficacy decreased by inhibiting L-arginine synthesis.CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions.ADSCs have higher L-arginine secretion,which leads to better angiogenesis induction and cardiac protection.ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.展开更多
Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre ...Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants.Col10a1-Cre;R26^(DTA/+)mice displayed dwarf phenotype,abnormal spongy bone,and significantly delayed drill-hole injuries healing,suggesting an indispensable role of HC lineage extension in bone growth and injury repair.Intriguingly,single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors(Pro-Angiogenic Descendants of HCs,PADs)among cells derived from Col10a1-Cre;R26^(DTA/+)and control femurs.In silico analysis of cell-cell communication supported Thrombospondin 4(THBS4)as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells.Concordantly,analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells,whereas Col10a1-Cre;R26^(DTA/+)mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4.Moreover,in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre;R26D TA/+metatarsal explants.Collectively,these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.展开更多
Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,th...Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,the additional functions of the bone vasculature,such as the secretion of various factors and the regulation of bone-related signaling pathways,are essential for maintaining bone health.In the bone microenvironment,bone tissue cells play a critical role in regulating angiogenesis,including osteoblasts,bone marrow mesenchymal stem cells(BMSCs),and osteoclasts.Osteogenesis and bone angiogenesis are closely linked.The decrease in osteogenesis and bone angiogenesis caused by aging leads to osteoporosis.Long noncoding RNAs(lncRNAs)are involved in various physiological processes,including osteogenesis and angiogenesis.Recent studies have shown that lncRNAs could mediate the crosstalk between angiogenesis and osteogenesis.However,the mechanism by which lncRNAs regulate angiogenesis-osteogenesis crosstalk remains unclear.In this review,we describe in detail the ways in which lncRNAs regulate the crosstalk between osteogenesis and angiogenesis to promote bone health,aiming to provide new directions for the study of the mechanism by which lncRNAs regulate bone metabolism.展开更多
BACKGROUND Stem cell therapy has been recognized as a promising strategy for enhancing cardiac function after myocardial infarction.Nonetheless,its clinical benefits are frequently limited by the poor survival and dif...BACKGROUND Stem cell therapy has been recognized as a promising strategy for enhancing cardiac function after myocardial infarction.Nonetheless,its clinical benefits are frequently limited by the poor survival and differentiation rates of the transplanted cells.AIM To clarify the role of hypoxia-inducible factor-1α(HIF-1α)/β-catenin in survival and angiogenesis of peripheral blood mesenchymal stem cells(PBMSCs).METHODS PBMSCs were isolated from rat abdominal aorta blood and characterized by multipotent differentiation assays.Cells were cultured under hypoxic conditions,followed by either overexpression or silencing of HIF-1α/β-catenin.Proliferative capacity was evaluated via colony formation assays,while cellular senescence was assessed usingβ-galactosidase staining.The protein and/or mRNA expressions of HIF-1α,β-catenin,basic fibroblast growth factor(bFGF),vascular endothelial growth factor(VEGF),survivin,Bcl2,Bax,cleaved caspase 3 were detected viawestern blotting and/or quantitative real-time polymerase chain reaction.PBMSCs co-expressing elevated HIF-1αandβ-catenin levels were transplanted into infarcted myocardial tissue to evaluate their therapeutic potential in vivo.RESULTS HIF-1αorβ-catenin overexpression enhanced self-renewal and inhibit apoptosis of PBMSCs by up-regulating Bcl2 and survivin,down-regulating Bax and cleaved-caspase 3.Besides,HIF-1αorβ-catenin overexpression elevated angiogenesis via increasing bFGF and VEGF expressions.Silence of HIF-1αorβ-catenin had opposite effect.Upregulation of HIF-1αincreasedβ-catenin expression,whereas modifications inβ-catenin did not influence HIF-1αexpression.Chromatin immunoprecipitation assay verified that HIF-1αdirectly modulatesβ-catenin transcription.In vivo,HIF-1αoverexpression significantly improved the retention of transplanted PBMSCs in infarcted myocardium and enhanced myocardial repair.Functional analysis further confirmed that HIF-1αoperated throughβ-catenin,which directly modulated the expression of bFGF,VEGF,survivin,Bcl2,Bax and cleaved caspase 3,thereby coordinating the anti-apoptotic and pro-angiogenic functions of transplanted PBMSCs.CONCLUSION This study highlights the modulatory function of HIF-1αon PBMSCs viaβ-catenin-driven anti-apoptotic and angiogenic signaling cascade under hypoxia environment,offering a promising strategy for improving the therapeutic effectiveness PBMSCs-based transplantation after myocardial infarction.展开更多
The pore structure of porous scaffolds plays a crucial role in bone repair.The prevalent bone implant structure in clinical practice is the traditional cubic structure.However,the traditional cubic structure exhibits ...The pore structure of porous scaffolds plays a crucial role in bone repair.The prevalent bone implant structure in clinical practice is the traditional cubic structure.However,the traditional cubic structure exhibits sharp edges and junctions that are not conducive to cell adhesion or growth.In this study,a double gyroid(DG)Ti6Al4V scaffold based on a triply periodic minimal surface(TPMS)structure was devised,and the osseointegration performance of DG structural scaffolds with varying porosities was investigated.Compression tests revealed that the elastic modulus and compressive strength of DG structural scaffolds were sufficient for orthopedic implants.In vitro cellular experiments demonstrated that the DG structure significantly enhanced cell proliferation,vascularization,and osteogenic differentiation compared to the cubic structure.The DG structure with 55%porosity exhibited the most favorable outcomes.In vivo experiments in rabbits further demonstrated that DG scaffolds could promote neovascularization and bone regeneration and maturation;those with 55%porosity performed best.Comparing the surface area,specific surface area per unit volume,and internal flow distribution characteristics of gyroid and DG structure scaffolds,the latter are more conducive to cell adhesion and growth within scaffolds.This study underscored the potential of DG scaffolds based on the TPMS structure in optimizing the pore structure design of titanium scaffolds,inducing angiogenesis,and advancing the clinical application of titanium scaffolds for repairing bone defects.展开更多
Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a ...Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue.Nb promotes bone formation and fracture healing,possibly by increasing vascular endothelial growth factor(VEGF)production.Nanoniobium particles(nNb)may promote angiogenesis.However,the effect of nNb on angiogenesis is unclear,limiting its application.This study confirmed that nNb significantly promoted angiogenesis.nNb increased and Ras-related C3 botulinum toxin substrate(Rac)family small guanosine triphosphatase(GTPase)1(Rac1)expression,inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration,further promoting angiogenesis.We discovered that cyclin-dependent kinase-like 5(CDKL5)is a new signaling molecule that activates Rac1.V-ets erythroblastosis virus E26 oncogene homolog(ETS)domain-containing protein(ELK1),regulating CDKL5 and Rac1,plays an upstream regulatory role.When ELK1 was inhibited,CDKL5 and Rac1 levels were decreased.ELK1,CDKL5 or Rac1 are effective regulatory targets of angiogenesis.Inhibiting expression of ELK1,CDKL5 or Rac1 decreased angiogenesis.Thus,nNb has good angiogenic effects.The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis.nNb can be used in bone tissue engineering as a new nanomaterial,and it will promote the development of a new strategy for tissue engineering.展开更多
Imprinted genes play a key role in regulating mammalian placental and embryonic development.Here,we generated glutaminyl-peptide cyclotransferase-knockout(Qpct^(-/-))mice utilizing the clustered regularly interspaced ...Imprinted genes play a key role in regulating mammalian placental and embryonic development.Here,we generated glutaminyl-peptide cyclotransferase-knockout(Qpct^(-/-))mice utilizing the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)platform and identified Qpct as a novel anti-angiogenic factor in regulating mouse placentation.Compared with Qpct^(+/+)mice,placentae and embryos(Qpct^(-/+)and Qpct^(-/-))showed significant overgrowth at embryonic Day 12.5(E12.5),E15.5,and E18.5.Using single-cell transcriptome analysis of 32309 cells from Qpct^(+/+)and Qpct^(-/-)mouse placentae,we identified 13 cell clusters via single-nucleus RNA sequencing(snRNA-seq)(8880 Qpct^(+/+)and 13577 Qpct^(-/-)cells)and 20 cell clusters via single-cell RNA sequencing(scRNA-seq)(6567 Qpct^(+/+)and 3285 Qpct^(-/-)cells).Furthermore,we observed a global up-regulation of pro-angiogenic genes in the Qpct^(-/-)background.Immunohistochemistry assays revealed a notable increase in the number of blood vessels in the decidual and labyrinthine layers of E15.5 Qpct^(-/+)and Qpct^(-/-)mice.Moreover,the elevation of multiple pairs of ligand-receptor interactions was observed in decidual cells,endothelial cells,and macrophages,promoting angiogenesis and inflammatory response.Our findings indicate that loss of maternal Qpct leads to altered phenotypic characteristics of placentae and embryos and promotes angiogenesis in murine placentae.展开更多
基金supported by the National Natural Science Foundation of China,No.32171356(to YW)Self-Support Research Projects of Shihezi University,No.ZZZC2021105(to WJ)+1 种基金Capital Medical University Natural Science Cultivation Fund,No.PYZ23044(to FQM)Beijing Municipal Natural Science Foundation,No.7244410(to JHD)。
文摘Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.
基金financially supported by the Adisseo Innovation Research Center for Nutrition and Health(060–2222319005)Natural Science Foundation of Sichuan(2023NSFSC1135)National Natural Science Foundation of China(31972603)。
文摘Background Previous evidence suggests that methionine(Met)consumption can promote placental angiogenesis and improve fetal survival.To investigate the mechanisms by which increased levels of Met as hydroxyl-Met(OHMet)improve placental function,forty sows were divided into four groups and fed either a control diet,or diets supplemented with 0.15%OHMet,0.3%OHMet or 0.3%Met(n=10).Placentas were collected immediately after expulsion,and extracted proteins were analyzed by tandem mass tag based quantitative proteomic analysis.Results We found that 0.15%OHMet consumption significantly increased placental vascular density compared with the control.Proteomic analysis identified 5,136 proteins,87 of these were differentially expressed(P<0.05,|fold change|>1.2).Enriched pathways in the Kyoto Encyclopedia of Genes and Genomes for 0.15%OHMet vs.control and 0.15%OHMet vs.0.3%OHMet were glutathione metabolism;for 0.15%OHMet vs.0.3%Met,they were NOD-like receptor signaling and apoptosis.Further analysis revealed that 0.15%OHMet supplementation upregulated the protein expression of glutathione-S-transferase(GSTT1)in placentas and trophoblast cells compared with the control and 0.3%OHMet groups,upregulated thioredoxin(TXN)in placentas and trophoblast cells compared with the 0.3%OHMet and 0.3%Met groups,and decreased reactive oxygen species(ROS)levels in trophoblast cells compared with other groups.In contrast,sows fed 0.3%OHMet or 0.3%Met diets increased placental interleukin 1βlevels compared with the control,and upregulated the protein expression of complex I-B9(NDUFA3)compared with the 0.15%OHMet group.Furthermore,homocysteine,an intermediate in the trans-sulphuration pathway of Met,damaged placental function by inhibiting the protein expression of TXN,leading to apoptosis and ROS production.Conclusion Although dietary 0.15%OHMet supplementation improved placental angiogenesis and increased antioxidative capacity,0.3%OHMet or 0.3%Met supplementation impaired placental function by aggravating inflammation and oxidative stress,which is associated with cumulative homocysteine levels.
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金supported by funding from the National Institutes of Health(R01 NS117510)(to RLM)。
文摘Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular networks.Brain vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the brain.This elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing vasculature.Brain capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.
文摘Exosomes(EXOs)play an important role in the progression of breast cancer.EXOs,with a diameter of approximately 100 nm,have a simple structure but diverse functions,and can affect the development of breast cancer through signal transduction and molecular transfer,etc.Angiogenesis provides nutrients for the growth and metastasis of breast cancer and is a crucial part of tumor progression.The mechanism of tumor angiogenesis is complex.The VEGF/VEGFR pathway promotes angiogenesis by regulating the activities of ECs.Hypoxia,a common feature in the tumor microenvironment,as a key regulator,can affect angiogenesis in multiple aspects such as the transfer of miRNAs in EXOs,protein transport,extracellular matrix regulation,and metabolic adaptation.The Notch pathway has a bidirectional regulatory role in breast cancer angiogenesis,and different molecules can promote or inhibit angiogenesis.EXOs secreted by breast cancer cells are rich in angiogenic factors.Components such as proteins and nucleic acids in EXOs can affect the functions and behaviors of vascular ECs,thereby influencing breast cancer angiogenesis.Research on the mechanisms of EXOs in breast cancer angiogenesis is of great significance for tumor treatment.EXOs are expected to become biomarkers for breast cancer diagnosis/prognosis.This research provides potential targets for in-depth understanding of the biological characteristics of breast cancer and the development of new treatment strategies.
基金supported by central government-guided major science and technology project of Hebei province 236Z7709G(M.C.Q.)Tangshan science and technology project 23130216E(M.C.Q.)+8 种基金key research projects of North China University of Science and Technology ZD-YG-202309(M.C.Q.)National Natural Science Foundations of China 82230030 and 81871492(Y.L.)Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)Beijing Natural Science Foundation L234017(Y.L.)Peking University Medicine plus X Pilot Program-Key Technologies R&D Project 2024YXXLHGG004(Y.L.)Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)First-Class Discipline Team of Kunming Medical University 2024XKTDTS08(Y.L.)Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Postdoctoral Fellowship Program of CPSF under Grant Number GZB20240038(X.J.C.).
文摘Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.
基金The National Key Research and Development Program of China,Grant/Award Number:2022YFF0710700Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01。
文摘Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and molecular changes remain unclear.This study investigated platelet-derived growth factor receptor beta-positive(Pdgfrb+)pericyte dynamics and reprogramming in GBM vasculature.Methods:We generated GL261-Luc and GL261-CFP glioblastoma cells via lentiviral transduction and established two transgenic models.(1)For pericyte labeling,Ai14 reporter mice was crossed with PDGFRβ-P2A-CreERT2mice for td Tomato-specific lineage tracing(PT mice).(2)For conditional ablation,we generated inducible Pdgfrb-expressing cell ablation models(PT mice was crossed with ROSA-DTA mice).An intravital imaging platform(FITC-dextran/CFP/td Tomato+two-photon microscopy)tracked pericytes,vessels,and tumor cells,while FACSsorted Pdgfrb+cells from GBM and normal brain were analyzed by LC-MS/MS proteomics.Results:Cre-mediated ablation of Pdgfrb-expressing cells revealed stage-dependent effects on GBM growth:early ablation inhibited progression while late ablation promoted it.Pericytes undergo dual spatial reorganization in GBM:regional enrichment with pre-sprouting accumulation at the tumor-brain interface,and focal positioning with preferential localization at vascular branch points.Concurrently,GBM vasculature displayed simplified branching,dilation,and pericyte remodeling(shorter processes,higher density).Proteomics revealed 1426 altered proteins,with upregulated proliferation pathways(e.g.,matrix metallopeptidase 14[Mmp14],lysyl oxidase like 2[Loxl2])and downregulated homeostasis functions(e.g.,transforming growth factor beta 1[Tgfb1]),validated by scRNA-seq in human GBM.Conclusions:This study demonstrates that during early GBM progression,pericytes actively drive tumor angiogenesis through molecular reprogramming toward proliferative and pro-angiogenic phenotypes,with the integrated imaging-proteomics framework revealing potential therapeutic targets for disrupting pericyte-mediated vascular remodeling.
基金supported by the National Natural Science Foundation of China (32102554)Sichuan Province “145” Breeding Tackle Project (2021YFYZ0008)China Agriculture Research System (CARS-35).
文摘Background Embryo implantation in early gestation is crucial for reproductive success,while dietary fiber plays a key role in regulating sow fertility.However,the underlying mechanisms remain unclear.This study explores the influence of dietary inulin on embryonic implantation using a sow model.Sows were fed a diet supplemented with 11 g/kg of inulin during early gestation and were slaughtered on gestation day 19(G19).Uterine fluid exosomes(UFEs)and endometrial tissues were collected for high-throughput sequencing and for analysis of the expression of angiogenesis-related genes and proteins,respectively.Furthermore,UFEs obtained from slaughtered sows were injected into G19 sows to investigate the effects on reproduction and angiogenesis.Results The results showed that inulin significantly increased the number of blood vessels in the endometrium and expression of the angiogenesis-related proteins MMP2 and ANGPT1 in G19 sows(P<0.05).Bioinformatics analysis revealed that inulin significantly downregulated miRNAs associated with angiogenesis inhibition in UFEs,while upregulating miRNAs related to trophoblast physiological activities and regulation of the uterine fluid microenvironment(P<0.05).Furthermore,intravenous injection of G19 sows with UFEs from sows fed a diet containing inulin had significantly promoted vascular formation in the endometrium and embryos,and increased the number of live embryos on gestation day 28(G28)(P<0.05).Additionally,the mRNA expression levels of MMP2,ANGPT1,and VEGF in the placentas of sows were significantly elevated on G28 and at farrowing in the UFEs injection group(P<0.05).Conclusion Dietary supplementation with inulin during early gestation in sows promoted embryo implantation by regulating angiogenesis at the maternal–fetal interface through the modulation of miRNA expression in UFEs.These findings provide a theoretical reference for the application of dietary fiber in sow nutrition.
基金supported by the Inha University Research Grant(to JKR).
文摘Pericytes are multifunctional mural cells that surround the abluminal wall of endothelial cells and are associated with vascular development,vascular permeability,and angiogenesis.Additionally,pericytes demonstrate stem cell-like properties and contribute to neuroinflammatory processes.Pericytes have been extensively studied in the central nervous system.However,specific mechanisms underlying its involvement in various physiological and pathological conditions,especially in erectile dysfunction(ED),remain poorly understood.Advancements in in vitro and in vitro techniques,such as single-cell RNA sequencing,are expanding our understanding of pericytes.Recent studies have shown that pericyte dysfunction is considered an important factor in the pathogenesis of vascular and neurological ED.Therefore,this study aims to analyze the specific role of pericytes in ED,focusing on diabetic and neurogenic ED.This article provides a comprehensive review of research findings on PubMed from 2000 to 2023,concerning pericyte dysfunction in the process of ED,offering valuable insights,and suggesting directions for further research.
基金financially supported by the Natural Science Foundation of Guangdong Province(No.2022A1515010307)the Science and Technology Planning Project of Guangzhou(Nos.2023A03J0693 and 2023A03J0040)
文摘Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disorder that was clinically treated by core decompression (CD) combined with bone grafting.However,the clinical outcome of this therapy for SONFH is usually unsatisfactory.Magnesium (Mg) is a biodegradable material reported as an ideal orthopedic implant.The Mg^(2+)released from its degradation is considered an effective factor for bone tissue formation,but the rapid degradation rate limited its application.Here,we reported a magnesiumDscandium (MgDSc) alloy for promoting bone regeneration in SONFH.We discovered that MgDSc alloy with satisfied corrosion resistance,antiapoptosis,angiogenic,and osteogenic properties in vitro,could facilitate osteogenic differentiation by activating the Wnt/β-catenin signaling pathway.In the clinically relevant SONFH model,CD combined with suitable MgDSc alloy implantation promoted angiogenesisDosteogenesis coupling and alleviated osteonecrosis.We observed fewer apoptotic osteocytes and empty bone lacunae,but more blood vessels and new bone formation in the Mg-Sc alloy implanted CD tunnel region compared with CD-treated SONFH rabbits.Properly degraded MgDSc alloy maintains high structural integrity and provides reliable mechanical support for the osteonecrotic femoral head,which is conducive to further clinical translation.
基金Supported by Nanchong Science and Technology Plan Project,No.23JCYJPT0064Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS590。
文摘BACKGROUND SLC16A8,a lactate efflux transporter,is upregulated in various cancers,but its effects on tumor microenvironments remain understudied.This research explores its role in colorectal cancer(CRC)and the impact on the associated microenvir-onment consisting of vascular endothelial cells.AIM To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.METHODS Hypoxic conditions prompted examination of SLC16A8 expression,glycolysis,lactate efflux,and Warburg effect correlations in CRC cell lines.Co-culture with HUVEC allowed for endothelial-mesenchymal transition(EndMT)character-ization,revealing lactate efflux's influence.Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments,investigating tumor growth,blood vessel distribution,and signaling pathway alterations.RESULTS SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression(P<0.05).Under hypoxic conditions,HIF-1αinduced SLC16A8 expression,leading to enhanced metabolic reprogramming and increased lactate production.siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes,including reduced glucose consumption and lactate production.Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells.In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth,reduced Ki67 expression,and decreased HIF-1αlevels.Furthermore,SLC16A8 silencing led to decreased ex-pression of key metabolic enzymes PKM2 and LDHA,indicating its role in glycolytic regulation.CONCLUSION Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.
基金supported by the National Natural Science Foundation of China(Grant No.81972288)the Scientific and Technologic Development Programme of Suzhou(Livelihood Science and Technology-Applied Basic Research in Healthcare,SYS2020057).
文摘Colorectal cancer(CRC)ranks among the top five most common malignant tumors worldwide and has a high mortality rate.Angiogenesis plays an important role in CRC progression;however,anti-angiogenesis therapy still has many limitations.Long non-coding RNAs(lncRNAs)participate in tumor progression by regulating the expression of vascular endothelial growth factor in metastatic CRC.Thus,targeting specific lncRNAs may provide some new hope for anti-angiogenic strategies.Through analyzing data from both clinical samples and The Cancer Genome Atlas database,we found that the lncRNA LINC01503 was specifically upregulated in CRC tissues and was associated with tumor progression and poor overall survival.We also demonstrated that LINC01503 enhanced the capacity for tube formation and migration of vascular endothelial cells,thus promoting CRC tumorigenesis by upregulating vascular endothelial growth factor A(VEGFA)expression in CRC cells.Mechanistically,LINC01503 promoted the expression of VEGFA by simultaneously regulating both mRNA and protein stability of VEGFA by binding to miR-342-3p and the chaperone HSP60,respectively.The upregulation of LINC01503 in CRC cells was attributed to the CREB-binding protein CBP/p300-mediated H3K27 acetylation of the LINC01503 promoter region.Taken together,our findings clarify the mechanism by which LINC01503 may promote CRC angiogenesis,implying that LINC01503 may serve as a potential prognostic biomarker and therapeutic target for CRC.
基金Supported by General Project of Xuzhou Science and Technology Bureau,No.KC22070.
文摘BACKGROUND Diabetic foot ulcers(DFU)are estimated to affect about 18.6 million people worldwide annually.The pathogenesis of DFU is complex,and the available drugs are not effective.Dl-3-n-butylphthalide(NBP)is a synthetic mixture of racemates used in China for the treatment of ischemic stroke.It was initially isolated from the seeds of Apium graveolens Linn,with studies showing its potential role in treating diabetes and its complications.AIM To predict and validate the mechanism by which NBP treats DFU.METHODS Network pharmacological analysis was performed to identify pharmacological targets and signaling pathways mediating the treatment effect of NBP on DFU.In vivo and in vitro experiments were conducted to validate the therapeutic effects and mechanisms of NBP on DFU.RESULTS Network pharmacology analysis identified 26 pharmacological targets of NBP and predicted that NBP could treat DFU partially by modulating apoptosis and vascular signaling pathways.Results from animal experiments showed that NBP significantly improved DFU by increasing neovascularization and fibroblast proliferation.In vitro tests demonstrated that NBP treatment promoted the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts,while inhibiting the apoptosis of human umbilical vein endothelial cells,human dermal fibroblasts,and human keratinocytes cells.CONCLUSION This study found that NBP could treat DFU by decreasing the rate of apoptosis and increasing angiogenesis via the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to the heme oxygenase 1,caspase 3,B cell leukemia/lymphoma 2,brain derived neurotrophic factor,and nuclear factor erythroid 2 L2 genes.
基金Supported by the National Natural Science Foundation of China,No.82472147the Key Research and Development Program of Heilongjiang Province of China,No.2023ZX06C04the Open Fund of Key Laboratory of Hepatosplenic Surgery,Ministry of Education,Harbin,China,No.GPKF202402.
文摘BACKGROUND Mesenchymal stem cell(MSC)-based therapy may be a future treatment for myocardial infarction(MI).However,few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs(ADSCs)obtained from elderly patients in comparison to that of bone marrow-derived MSCs(BMSCs)from the same elderly patients.The metabolomics results revealed a significantly higher Larginine excretion from aged ADSCs vs BMSCs in hypoxic conditions.This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed.Then,arginine succinate lyase(ASL)overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs.Subsequently,in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control,BMSCs,BMSCs ASL short hairpin RNA,BMSCs ASL overexpressed,and BMSC negative control on cocultured human umbilical vein endothelial cells.All sample sizes,which were determined to meet the statistical requirements and be greater than 3,were established on the basis of previously established literature standards.The protein levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor,etc.were detected.In vivo,the five types of cells were transplanted into the infarcted area of MI rat models,and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.RESULTS Metabolomic analysis showed that L-arginine was increased.Using ASL gene transfection,we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro,which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression,VEGF and basic fibroblast growth factor secretion,and inductive angiogenesis to levels comparable to donor-matched ADSCs.After the cell transplantation in vivo,the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells,enhanced vessel formation,reduced scar size,and improved cardiac function in the MI rat model.The therapeutic efficacy decreased by inhibiting L-arginine synthesis.CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions.ADSCs have higher L-arginine secretion,which leads to better angiogenesis induction and cardiac protection.ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.
基金financial support from the National Natural Science Foundation of China(grants 82394442,82422043,82272442)the Key Industrial Chain Program of Shaanxi,China(No.2022ZDLSF02-12)。
文摘Hypertrophic chondrocytes(HCs)could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown.Here,we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants.Col10a1-Cre;R26^(DTA/+)mice displayed dwarf phenotype,abnormal spongy bone,and significantly delayed drill-hole injuries healing,suggesting an indispensable role of HC lineage extension in bone growth and injury repair.Intriguingly,single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors(Pro-Angiogenic Descendants of HCs,PADs)among cells derived from Col10a1-Cre;R26^(DTA/+)and control femurs.In silico analysis of cell-cell communication supported Thrombospondin 4(THBS4)as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells.Concordantly,analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells,whereas Col10a1-Cre;R26^(DTA/+)mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4.Moreover,in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre;R26D TA/+metatarsal explants.Collectively,these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.
基金supported by the National Natural Science Foundation of China(No.81901430)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515010379)+1 种基金the Science and Technology Projects in Guangzhou(No.2023A04J0555)the Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion(No.2021B1212040014),China.
文摘Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,the additional functions of the bone vasculature,such as the secretion of various factors and the regulation of bone-related signaling pathways,are essential for maintaining bone health.In the bone microenvironment,bone tissue cells play a critical role in regulating angiogenesis,including osteoblasts,bone marrow mesenchymal stem cells(BMSCs),and osteoclasts.Osteogenesis and bone angiogenesis are closely linked.The decrease in osteogenesis and bone angiogenesis caused by aging leads to osteoporosis.Long noncoding RNAs(lncRNAs)are involved in various physiological processes,including osteogenesis and angiogenesis.Recent studies have shown that lncRNAs could mediate the crosstalk between angiogenesis and osteogenesis.However,the mechanism by which lncRNAs regulate angiogenesis-osteogenesis crosstalk remains unclear.In this review,we describe in detail the ways in which lncRNAs regulate the crosstalk between osteogenesis and angiogenesis to promote bone health,aiming to provide new directions for the study of the mechanism by which lncRNAs regulate bone metabolism.
基金Guangdong Provincial Natural Science Foundation General Program,No.2025A1515012455Guangzhou Municipal Science and Technology Project,No.2024A03J0653,No.2023A03J0595,No.2023A03J0510,No.2023A03J0528.
文摘BACKGROUND Stem cell therapy has been recognized as a promising strategy for enhancing cardiac function after myocardial infarction.Nonetheless,its clinical benefits are frequently limited by the poor survival and differentiation rates of the transplanted cells.AIM To clarify the role of hypoxia-inducible factor-1α(HIF-1α)/β-catenin in survival and angiogenesis of peripheral blood mesenchymal stem cells(PBMSCs).METHODS PBMSCs were isolated from rat abdominal aorta blood and characterized by multipotent differentiation assays.Cells were cultured under hypoxic conditions,followed by either overexpression or silencing of HIF-1α/β-catenin.Proliferative capacity was evaluated via colony formation assays,while cellular senescence was assessed usingβ-galactosidase staining.The protein and/or mRNA expressions of HIF-1α,β-catenin,basic fibroblast growth factor(bFGF),vascular endothelial growth factor(VEGF),survivin,Bcl2,Bax,cleaved caspase 3 were detected viawestern blotting and/or quantitative real-time polymerase chain reaction.PBMSCs co-expressing elevated HIF-1αandβ-catenin levels were transplanted into infarcted myocardial tissue to evaluate their therapeutic potential in vivo.RESULTS HIF-1αorβ-catenin overexpression enhanced self-renewal and inhibit apoptosis of PBMSCs by up-regulating Bcl2 and survivin,down-regulating Bax and cleaved-caspase 3.Besides,HIF-1αorβ-catenin overexpression elevated angiogenesis via increasing bFGF and VEGF expressions.Silence of HIF-1αorβ-catenin had opposite effect.Upregulation of HIF-1αincreasedβ-catenin expression,whereas modifications inβ-catenin did not influence HIF-1αexpression.Chromatin immunoprecipitation assay verified that HIF-1αdirectly modulatesβ-catenin transcription.In vivo,HIF-1αoverexpression significantly improved the retention of transplanted PBMSCs in infarcted myocardium and enhanced myocardial repair.Functional analysis further confirmed that HIF-1αoperated throughβ-catenin,which directly modulated the expression of bFGF,VEGF,survivin,Bcl2,Bax and cleaved caspase 3,thereby coordinating the anti-apoptotic and pro-angiogenic functions of transplanted PBMSCs.CONCLUSION This study highlights the modulatory function of HIF-1αon PBMSCs viaβ-catenin-driven anti-apoptotic and angiogenic signaling cascade under hypoxia environment,offering a promising strategy for improving the therapeutic effectiveness PBMSCs-based transplantation after myocardial infarction.
基金supported bythe National Natural Science Foundation of China(Nos.U23A20523,82272504,and 82072456)the Department of Science and Technology of Jilin Province,China(Nos.20210101439JC,20210101321JC,20220204119YY,202201ZYTS131,202201ZYTS129,20230204114YY,YDZJ202201ZYTS505,and YDZJ202301ZYTS076)+4 种基金the Special Program for Science and Technology Personnel of Changchun(No.ZKICKJJ2023015)the Key Training Plan for Outstanding Youth of Jilin University(No.419070623036)the Research Fund of the First Hospital of Jilin University(No.2021-zl-01)the Graduate Innovation Fund of Jilin University(No.2024CX125)the Foun-dation of National Center for Translational Medicine(Shanghai)SHU Branch,China(No.SUITM-202405).
文摘The pore structure of porous scaffolds plays a crucial role in bone repair.The prevalent bone implant structure in clinical practice is the traditional cubic structure.However,the traditional cubic structure exhibits sharp edges and junctions that are not conducive to cell adhesion or growth.In this study,a double gyroid(DG)Ti6Al4V scaffold based on a triply periodic minimal surface(TPMS)structure was devised,and the osseointegration performance of DG structural scaffolds with varying porosities was investigated.Compression tests revealed that the elastic modulus and compressive strength of DG structural scaffolds were sufficient for orthopedic implants.In vitro cellular experiments demonstrated that the DG structure significantly enhanced cell proliferation,vascularization,and osteogenic differentiation compared to the cubic structure.The DG structure with 55%porosity exhibited the most favorable outcomes.In vivo experiments in rabbits further demonstrated that DG scaffolds could promote neovascularization and bone regeneration and maturation;those with 55%porosity performed best.Comparing the surface area,specific surface area per unit volume,and internal flow distribution characteristics of gyroid and DG structure scaffolds,the latter are more conducive to cell adhesion and growth within scaffolds.This study underscored the potential of DG scaffolds based on the TPMS structure in optimizing the pore structure design of titanium scaffolds,inducing angiogenesis,and advancing the clinical application of titanium scaffolds for repairing bone defects.
基金supported by Guangzhou Science and Technology Plan Project(No.2023A03J0328)the National Natural Science Foundation of China(No.81600904)。
文摘Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue.Nb promotes bone formation and fracture healing,possibly by increasing vascular endothelial growth factor(VEGF)production.Nanoniobium particles(nNb)may promote angiogenesis.However,the effect of nNb on angiogenesis is unclear,limiting its application.This study confirmed that nNb significantly promoted angiogenesis.nNb increased and Ras-related C3 botulinum toxin substrate(Rac)family small guanosine triphosphatase(GTPase)1(Rac1)expression,inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration,further promoting angiogenesis.We discovered that cyclin-dependent kinase-like 5(CDKL5)is a new signaling molecule that activates Rac1.V-ets erythroblastosis virus E26 oncogene homolog(ETS)domain-containing protein(ELK1),regulating CDKL5 and Rac1,plays an upstream regulatory role.When ELK1 was inhibited,CDKL5 and Rac1 levels were decreased.ELK1,CDKL5 or Rac1 are effective regulatory targets of angiogenesis.Inhibiting expression of ELK1,CDKL5 or Rac1 decreased angiogenesis.Thus,nNb has good angiogenic effects.The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis.nNb can be used in bone tissue engineering as a new nanomaterial,and it will promote the development of a new strategy for tissue engineering.
基金supported by the National Natural Science Foundation of China(No.32271165)the Interdisciplinary Project in Ocean Research of Tongji University(No.2022-2-ZD-02),China.
文摘Imprinted genes play a key role in regulating mammalian placental and embryonic development.Here,we generated glutaminyl-peptide cyclotransferase-knockout(Qpct^(-/-))mice utilizing the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)platform and identified Qpct as a novel anti-angiogenic factor in regulating mouse placentation.Compared with Qpct^(+/+)mice,placentae and embryos(Qpct^(-/+)and Qpct^(-/-))showed significant overgrowth at embryonic Day 12.5(E12.5),E15.5,and E18.5.Using single-cell transcriptome analysis of 32309 cells from Qpct^(+/+)and Qpct^(-/-)mouse placentae,we identified 13 cell clusters via single-nucleus RNA sequencing(snRNA-seq)(8880 Qpct^(+/+)and 13577 Qpct^(-/-)cells)and 20 cell clusters via single-cell RNA sequencing(scRNA-seq)(6567 Qpct^(+/+)and 3285 Qpct^(-/-)cells).Furthermore,we observed a global up-regulation of pro-angiogenic genes in the Qpct^(-/-)background.Immunohistochemistry assays revealed a notable increase in the number of blood vessels in the decidual and labyrinthine layers of E15.5 Qpct^(-/+)and Qpct^(-/-)mice.Moreover,the elevation of multiple pairs of ligand-receptor interactions was observed in decidual cells,endothelial cells,and macrophages,promoting angiogenesis and inflammatory response.Our findings indicate that loss of maternal Qpct leads to altered phenotypic characteristics of placentae and embryos and promotes angiogenesis in murine placentae.
