Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The express...Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.展开更多
Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applicat...Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.展开更多
Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesi...Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.展开更多
The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here,...The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 （PHF20） functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Casg-based targeted knockout （KO） for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem ceU-Uke traits. Mechanistically, PHF20 interacts with poly（ADP-ribose） polymerase 1 （PARP1） and directly binds to promoter regions of octamer-binding transcription factor 4 （OCT4） and sex determining region Y-box 2 （SOX2） to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit （H3K4me3）. Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.展开更多
Bromodomain-containing proteins are known readers of histone acetylation that regulate chromatin structure and transcription.Although the functions of bromodomain-containing proteins in development,homeostasis,and dis...Bromodomain-containing proteins are known readers of histone acetylation that regulate chromatin structure and transcription.Although the functions of bromodomain-containing proteins in development,homeostasis,and disease states have been well studied,their role in self-renewal of hematopoietic stem and progenitor cells(HSPCs)remains poorly understood.Here,we performed a chemical screen using nine bromodomain inhibitors and found that the bromodomain and PHD finger-containing protein 1(Brpf1)inhibitor OF-1 enhanced the expansion of Lin−Sca-1+c-Kit+HSPCs ex vivo without skewing their lineage differentiation potential.Importantly,our results also revealed distinct functions of Brpf1 isoforms in HSPCs.Brpf1b promoted the expansion of HSPCs.By contrast,Brpf1a is the most abundant isoform in adult HSPCs but enhanced HSPC quiescence and decreased the HSPC expansion.Furthermore,inhibition of Brpf1a by OF-1 promoted histone acetylation and chromatin accessibility leading to increased expression of self-renewal-related genes(e.g.Mn1).The phenotypes produced by OF-1 treatment can be rescued by suppression of Mn1 in HSPCs.Our findings demonstrate that this novel bromodomain inhibitor OF-1 can promote the clinical application of HSPCs in transplantation.展开更多
Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events.It has been shown that the occurrence of calcium oxalate monohydrate(COM)during stone formation is regulated by cr...Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events.It has been shown that the occurrence of calcium oxalate monohydrate(COM)during stone formation is regulated by crystal growth modifiers.Although crystallization inhibitors have been recognized as a therapeutic modality for decades,limited progress has been made in the discovery of effective modifiers to intervene with stone disease.In this study,we have used metabolomics technologies,a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model.By in-depth mining and analysis of metabolomics data,we have screened five differential metabolites.Through density functional theory studies and bulk crystallization,we found that three of them(salicyluric,gentisic acid and succinate)could effectively inhibit nucleation in vitro.We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones.Notably,succinate,a key player in the tricarboxylic acid cycle,could decrease kidney calcium deposition and injury in the model.Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation,inhibition of cell adhesion and osteogenic differentiation.These findings indicated that succinate may provide a new therapeutic option for urinary stones.展开更多
Urine-derived stem cells(USCs)have shown potentials for the treatment of skeletal and urological disorders.Based on published literature and our own data,USCs consist of heterogeneous populations of cells.In this pape...Urine-derived stem cells(USCs)have shown potentials for the treatment of skeletal and urological disorders.Based on published literature and our own data,USCs consist of heterogeneous populations of cells.In this paper,we identify and characterize two morphologically distinct subpopulations of USCs from human urine samples,named as spindle-shaped USCs(SS-USCs)and rice-shaped USCs(RS-USCs)respectively.The two subpopulations showed similar clone-forming efficiency,while SS-USCs featured faster proliferation,higher motility,and greater potential for osteogenic and adipogenic differentiation,RS-USCs showed greater potential for chondrogenic differentiation.POU5F1 was strongly expressed in both subpopulations,but MYC was weakly expressed.Both subpopulations showed similar patterns of CD24,CD29,CD34,CD44,CD73,CD90 and CD105 expression,while a higher percentage of RS-USCs were positive for CD133.SS-USCs were positive for VIM,weakly positive for SLC12A1 and UMOD,and negative for KRT18,NPHS1,AQP1 and AQP2,indicating a renal mesenchyme origin;while RSUSCs are positive for VIM,partially positive for KRT18,NPHS1,AQP1,SLC12A1 and UMOD,and negative for AQP2,indicating a nephron tubule origin.The above results can facilitate understanding of the biological characteristics of subpopulations of USCs,and provide a basis for further research and applications of such cells.展开更多
Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine effects.Exosomes,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized ...Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine effects.Exosomes,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized membranous vesicles containing diverse bioactive cargoes.With the potent ability of modulating skin cell behaviors,MSC-derived exosomes(MSC-Exos)are regarded as a promising nanomaterial for regenerative wound therapy.Under hostile conditions,MSC-Exos are efficient in protecting skin cells from severe damage and restoring their function.According to recent studies,MSC-Exos possess remarkable pro-healing effects in a variety of skin wounds,typically resulting in increased wound closure,inhibited scar tissue formation,and better restoration of skin function.To further enhance the therapeutic potential of MSC-Exos,the development of applicable pretreatment strategies and the optimization of exosome delivery are under intensive investigation.Herein,we summarize current research progress of MSC-Exos for skin wound treatment,with an emphasis on the biological effects of these nanovesicles,the repair mechanisms,and future challenges in clinical translation.展开更多
Injection laryngoplasty with biomaterials is an effective technique to treat glottic insufficiency.However,the inadequate durability,deficient pro-secretion of extracellular matrix(ECM)and poor functional preservation...Injection laryngoplasty with biomaterials is an effective technique to treat glottic insufficiency.However,the inadequate durability,deficient pro-secretion of extracellular matrix(ECM)and poor functional preservation of current biomaterials have yielded an unsatisfactory therapeutic effect.Herein,a self-fusing bioactive hydrogel comprising modified carboxymethyl chitosan and sodium alginate is developed through a dual-crosslinking mechanism(photo-triggered and dynamic covalent bonds).Owing to its characteristic networks,the synergistic effect of the hydrogel for vocal folds(VFs)vibration and phonation is adequately demonstrated.Notably,owing to its inherent bioactivity of polysaccharides,the hydrogel could significantly enhance the secretion of major components(type I/III collagen and elastin)in the lamina propria of the VFs both in vivo and in vitro.In a rabbit model for glottic insufficiency,the optimized hydrogel(C1A1)has demonstrated a durability far superior to that of the commercially made hyaluronic acid(HA)Gel.More importantly,owing to the ECM-inducing bioactivity,the physiological functions of the VFs treated with the C1A1 hydrogel also outperformed that of the HA Gel,and were similar to those of the normal VFs.Taken together,through a simple-yet-effective strategy,the novel hydrogel has demonstrated outstanding durability,ECM-inducing bioactivity and physiological function preservation,therefore has an appealing clinical value for treating glottic insufficiency.展开更多
As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount...As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount of research on the topic,the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored,though many aspects still remain unclear.In this review,we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin,bone and articular cartilage repair.In addition to the identification procedure of USCs,we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs.Potential concerns and perspectives have also been summarized.展开更多
The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes.Biomaterials such as submucosa of small intestine(SIS)have been widel...The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes.Biomaterials such as submucosa of small intestine(SIS)have been widely used as patches for bladder repair,but the outcomes are not fully satisfactory.To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization.In this study,we have developed an anti-CD29 antibody-conjugated SIS scaffold(AC-SIS)which is capable of specifically capturing urine-derived stem cells(USCs)in situ for tissue repair and regeneration.The scaffold has exhibited effective capture capacity and sound biocompatibility.In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration.The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.展开更多
Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone...Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.展开更多
Approximately 25%of patients with congenital heart disease require implantation of patches to repair.However,most of the currently available patches are made of inert materials with unmatched electrical conductivity a...Approximately 25%of patients with congenital heart disease require implantation of patches to repair.However,most of the currently available patches are made of inert materials with unmatched electrical conductivity and mechanical properties,which may lead to an increased risk for arrhythmia and heart failure.In this study,we have developed a novel Polyurethane/Small intestinal submucosa patch(PSP)with mechanical and electrical properties similar to those of the native myocardial tissue,and assessed its feasibility for the reconstruction of right ventricular outflow tract.A right ventricular outflow tract reconstruction model was constructed in 40 rabbits.Compared with commercially available bovine pericardium patch,the PSP patch has shown better histocompatibility and biodegradability,in addition with significantly improved cardiac function.To tackle the significant fibrosis and relatively poor vascularization during tissue remodeling,we have further developed a bioactive patch by incorporating the PSP composites with urine-derived stem cells(USCs)which were pretreated with hypoxia.The results showed that the hypoxia-pretreated bioactive patch could significantly inhibit fibrosis and promote vascularization and muscularization,resulting in better right heart function.Our findings suggested that the PSP patch combined with hypoxia-pretreated USCs may provide a better strategy for the treatment of congenital heart disease.展开更多
Developing highly bioactive scaffold materials to promote stem cell migration,proliferation and tissue-specific differentiation is a crucial requirement in current tissue engineering and regenerative medicine.Our prev...Developing highly bioactive scaffold materials to promote stem cell migration,proliferation and tissue-specific differentiation is a crucial requirement in current tissue engineering and regenerative medicine.Our previous work has demonstrated that the decellularized tendon slices(DTSs)are able to promote stem cell proliferation and tenogenic differentiation in vitro and show certain pro-regenerative capacity for rotator cuff tendon regeneration in vivo.In this study,we present a strategy to further improve the bioactivity of the DTSs for constructing a novel highly bioactive tendon-regenerative scaffold by surface modification of tendon-specific stem cell-derived extracellular matrix(tECM),which is expected to greatly enhance the capacity of scaffold material in regulating stem cell behavior,including migration,proliferation and tenogenic differentiation.We prove that the modification of tECM could change the highly aligned surface topographical cues of the DTSs,retain the surface stiffness of the DTSs and significantly increase the content of multiple ECM components in the tECM-DTSs.As a result,the tECM-DTSs dramatically enhance the migration,proliferation as well as tenogenic differentiation of rat bone marrow-derived stem cells compared with the DTSs.Collectively,this strategy would provide a new way for constructing ECMbased biomaterials with enhanced bioactivity for in situ tendon regeneration applications.展开更多
Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism a...Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine.Nevertheless,limited yield has restrained full explication of their functions and clinical applications.To address this,various attempts have been made to explore the up-and down-stream manipulations in a bid to increase the production of exosomes.This review has recapitulated factors which may influence the yield of stem cell-derived exosomes,including selection and culture of stem cells,isolation and preservation of the exosomes,and development of artificial exosomes.展开更多
Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach i...Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.展开更多
Endoscopic submucosal dissection (ESD) for gastrointestinal tumors and premalignant lesions needs submucosal fluid cushion (SFC) for mucosal uplift before dissection, and wound care including wound closure and rapid h...Endoscopic submucosal dissection (ESD) for gastrointestinal tumors and premalignant lesions needs submucosal fluid cushion (SFC) for mucosal uplift before dissection, and wound care including wound closure and rapid healing postoperatively. Current SFC materials as well as materials and/or methods for post-ESD wound care have single treatment effect and hold corresponding drawbacks, such as easy dispersion, short duration, weak hemostasis and insufficient repair function. Thus, designing materials that can serve as both SFC materials and wound care is highly desired, and remains a challenge. Herein, we report a two-component in-situ hydrogel prepared from maleimide-based oxidized sodium alginate and sulfhydryl carboxymethyl-chitosan, which gelated mainly based on "click" chemistry and Schiff base reaction. The hydrogels showed short gelation time, outstanding tissue adhesion, favorable hemostatic properties, and good biocompatibility. A rat subcutaneous ultrasound model confirmed the ability of suitable mucosal uplift height and durable maintenance time of AM solution. The in vivo/in vitro rabbit liver hemorrhage model demonstrated the effects of hydrogel in rapid hemostasis and prevention of delayed bleeding. The canine esophageal ESD model corroborated that the in-situ hydrogel provided good mucosal uplift and wound closure effects, and significantly accelerated wound healing with accelerating re-epithelization and ECM remodeling post-ESD. The two-component in-situ hydrogels exhibited great potential in gastrointestinal tract ESD.展开更多
Progranulin(PGRN)is a multifunctional growth factor involved in many physiolog-ical processes and disease states.The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progre...Progranulin(PGRN)is a multifunctional growth factor involved in many physiolog-ical processes and disease states.The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis(OA)led us to investi-gate the role of PGRN in the regulation of chondrocyte autophagy.PGRN knockout chondro-cytes exhibited a deficient autophagic response with limited induction following rapamycin,serum starvation,and IL-1b-induced autophagy.PGRN-mediated anabolism and suppression of IL-1b-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor.Mechanistically,during the process of OA,PGRN and the ATG5eATG12 conjugate form a protein complex;PGRN regulates autophagy in chondrocytes and OA through,at least partially,the interactions between PGRN and the ATG5eATG12 conjugate.Furthermore,the ATG5eATG12 conjugate is critical for cell proliferation and apoptosis.Knockdown or knockout of ATG5 reduces the expression of ATG5eATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism.Overexpression of PGRN partially reversed this effect.In brief,the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA.Such studies provide new insights into the pathogen-esis of OA and PGRN-associated autophagy in chondrocyte homeostasis.展开更多
In the present study,tissue blocks were randomly sampled from the entire hippocampus of 6-week-old Long-Evans rats.Isotropic,uniform and random sections,60 nm thick,were prepared by isector.Fifteen fields of view were...In the present study,tissue blocks were randomly sampled from the entire hippocampus of 6-week-old Long-Evans rats.Isotropic,uniform and random sections,60 nm thick,were prepared by isector.Fifteen fields of view were randomly selected for each section and photographed using a transmission electron microscope.The mean internal and external diameters of the myelin sheaths were obtained by measuring the longest profile diameter perpendicular to its longest axis.The inner and outer perimeters of the myelin sheaths were estimated using the equidistant parallel test lines.The thickness of the myelin sheaths was estimated by direct orthogonal measurements in uniform,random locations.These stereological methods should permit an unbiased quantitative assessment of changes in the myelin sheaths of myelinated fibers in the hippocam-pus.展开更多
Chemotherapy may cause cellular oxidative stress to bone marrow.Oxidative damage of bone marrow hematopoietic microenvironment is closely related to chronic myelosuppression after chemotherapeutic treatment.Angelica s...Chemotherapy may cause cellular oxidative stress to bone marrow.Oxidative damage of bone marrow hematopoietic microenvironment is closely related to chronic myelosuppression after chemotherapeutic treatment.Angelica sinensis polysaccharides(ASP)are major effective ingredients of traditional Chinese medicine Angelica with multi-target anti-oxidative stress features.In the current study,we investigated the protective roles and mechanisms of ASP on chemotherapy-induced bone marrow stromal cell(BMSC)damage.The human bone marrow stromal cell line HS-5 cells were divided into control group,5-FU group,5-FU+ASP group,and 5-FU+LiCl group to investigate the mechanism of ASP to alleviate 5-FU-induced BMSC proliferation inhibition.The results showed that 5-FU inhibits the growth of HS-5 cells in a time and dose-dependent manner;however,ASP partially counteracted the 5-FU-induced decrease in cell viability,whereas Wnt signaling inhibitor Dkk1 antagonized the effect of ASP on HS-5 cells.ASP reversed the decrease in total cytoplasmicβ-catenin,p-GSK-3β,and CyclinD1 following 5-FU treatment and modulated nuclear expression ofβ-catenin,Lef-1,and C-myc proteins.Furthermore,ASP also enhanced the antioxidant capacity of cells and reduced 5-FU-induced oxidative stress,attenuated FoxO1 expression,thus weakened its downstream apoptosis-related proteins and G0/G1 checkpoint-associated p27^(Kip1) expression to alleviate 5-FU-induced apoptosis and to promote cell cycle progression.All the results above suggest that the protective role of ASP in 5-FU-treated BMSCs proliferation for the chemotherapy may be related to its activating Wnt/β-catenin signaling and keeping homeostasis betweenβ-catenin and FoxO1 under oxidative stress.The study provides a potential therapeutic strategy for alleviating chemotherapeutic damage on BMSCs.展开更多
文摘Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.
基金supported by Natural Science Foundation of Sichuan Province,Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010002)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037).
文摘Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.
基金This work was supported by grants from the National Natural Science Foundation of China(No.82170924)the National Key R&D Program of China(No.2021YFA1100600)+2 种基金the Pearl River Talent Recruitment Program(Nos.2019ZT08Y485 and 2019JC01Y138)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,C-03 and D-11)the Sun Yat-sen University Young Teacher Key Cultivation Project(No.18ykzd05).
文摘Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.
基金This work was supported by grants from the National Natural Science Foundation of China （81572766 and 31771630）, the National Key Research and Development Program of China （2017YFA0103800）, Guangdong Innovative and Entrepreneurial Research Team Program （2016ZT06S029）, Guangdong Natural Science Foundation （2016A030313215 and 2016A030313238）, SYSU Young Teachers Training Program （16YKZD14） and grants （CA101795 and IU54CA210181） from U.S. National Cancer Institute, National Institutes of Health （NIH）, DOD （W81XWH-16- 1-0417）, and CPRIT （DP150099, RP170537, and RP150611）.
文摘The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 （PHF20） functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Casg-based targeted knockout （KO） for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem ceU-Uke traits. Mechanistically, PHF20 interacts with poly（ADP-ribose） polymerase 1 （PARP1） and directly binds to promoter regions of octamer-binding transcription factor 4 （OCT4） and sex determining region Y-box 2 （SOX2） to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit （H3K4me3）. Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.
基金supported by National Key Research and Development Program of China(2017YFA0103802)the National Natural Science Foundation of China(81700100,31771630,81572766,81702784,and 81802974)+2 种基金Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029)Natural Science Foundation of Guangdong Provinee(2017A030312009 and 2016A030313238)Special Funds for Dapeng New District Industry Development(KY20160309).
文摘Bromodomain-containing proteins are known readers of histone acetylation that regulate chromatin structure and transcription.Although the functions of bromodomain-containing proteins in development,homeostasis,and disease states have been well studied,their role in self-renewal of hematopoietic stem and progenitor cells(HSPCs)remains poorly understood.Here,we performed a chemical screen using nine bromodomain inhibitors and found that the bromodomain and PHD finger-containing protein 1(Brpf1)inhibitor OF-1 enhanced the expansion of Lin−Sca-1+c-Kit+HSPCs ex vivo without skewing their lineage differentiation potential.Importantly,our results also revealed distinct functions of Brpf1 isoforms in HSPCs.Brpf1b promoted the expansion of HSPCs.By contrast,Brpf1a is the most abundant isoform in adult HSPCs but enhanced HSPC quiescence and decreased the HSPC expansion.Furthermore,inhibition of Brpf1a by OF-1 promoted histone acetylation and chromatin accessibility leading to increased expression of self-renewal-related genes(e.g.Mn1).The phenotypes produced by OF-1 treatment can be rescued by suppression of Mn1 in HSPCs.Our findings demonstrate that this novel bromodomain inhibitor OF-1 can promote the clinical application of HSPCs in transplantation.
基金This study has been jointly sponsored by the National Natural Science Foundation of China(Grant No.32171351)the“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002)+2 种基金Med-X Innovation Program of Med-X Center for Materials,Sichuan University(Grant No.MCM202104)the Project funded by China Postdoctoral Science Foundation(2022M722277)the Sichuan University postdoctoral interdisciplinary Innovation Fund.We thank Ms.Lei Wu and Bo Su from Histology and Imaging Platform,Core Facilities of West China,Sichuan University,Mr.Yun-fei Tian and Shu-guang Yan from the Analytical&Testing Center of Sichuan University,Sichuan University,and Ms.Nian-guo Zhu from Institute of Respiratory Health,West China Hospital,Sichuan University for the technique supports.We thank Xi-jing Yang and Xiao-ting Chen form the Animal Experimental Center of West China Hospital for assistance in animal experiments.
文摘Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events.It has been shown that the occurrence of calcium oxalate monohydrate(COM)during stone formation is regulated by crystal growth modifiers.Although crystallization inhibitors have been recognized as a therapeutic modality for decades,limited progress has been made in the discovery of effective modifiers to intervene with stone disease.In this study,we have used metabolomics technologies,a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model.By in-depth mining and analysis of metabolomics data,we have screened five differential metabolites.Through density functional theory studies and bulk crystallization,we found that three of them(salicyluric,gentisic acid and succinate)could effectively inhibit nucleation in vitro.We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones.Notably,succinate,a key player in the tricarboxylic acid cycle,could decrease kidney calcium deposition and injury in the model.Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation,inhibition of cell adhesion and osteogenic differentiation.These findings indicated that succinate may provide a new therapeutic option for urinary stones.
基金supported by the National Key Research&Development Program of China(2017YFC1104702)the National Natural Science Foundation of China(31771065,31600792,81473446)+1 种基金the Sichuan Science and Technology Program(2019JDRC0020)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC18002)。
文摘Urine-derived stem cells(USCs)have shown potentials for the treatment of skeletal and urological disorders.Based on published literature and our own data,USCs consist of heterogeneous populations of cells.In this paper,we identify and characterize two morphologically distinct subpopulations of USCs from human urine samples,named as spindle-shaped USCs(SS-USCs)and rice-shaped USCs(RS-USCs)respectively.The two subpopulations showed similar clone-forming efficiency,while SS-USCs featured faster proliferation,higher motility,and greater potential for osteogenic and adipogenic differentiation,RS-USCs showed greater potential for chondrogenic differentiation.POU5F1 was strongly expressed in both subpopulations,but MYC was weakly expressed.Both subpopulations showed similar patterns of CD24,CD29,CD34,CD44,CD73,CD90 and CD105 expression,while a higher percentage of RS-USCs were positive for CD133.SS-USCs were positive for VIM,weakly positive for SLC12A1 and UMOD,and negative for KRT18,NPHS1,AQP1 and AQP2,indicating a renal mesenchyme origin;while RSUSCs are positive for VIM,partially positive for KRT18,NPHS1,AQP1,SLC12A1 and UMOD,and negative for AQP2,indicating a nephron tubule origin.The above results can facilitate understanding of the biological characteristics of subpopulations of USCs,and provide a basis for further research and applications of such cells.
基金supported by the National Natural Science Foundation of China(Nos.32071331 and 31600792)Post-Doctor Research Project,West China Hospital,Sichuan University(No.2018HXBH053).
文摘Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine effects.Exosomes,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized membranous vesicles containing diverse bioactive cargoes.With the potent ability of modulating skin cell behaviors,MSC-derived exosomes(MSC-Exos)are regarded as a promising nanomaterial for regenerative wound therapy.Under hostile conditions,MSC-Exos are efficient in protecting skin cells from severe damage and restoring their function.According to recent studies,MSC-Exos possess remarkable pro-healing effects in a variety of skin wounds,typically resulting in increased wound closure,inhibited scar tissue formation,and better restoration of skin function.To further enhance the therapeutic potential of MSC-Exos,the development of applicable pretreatment strategies and the optimization of exosome delivery are under intensive investigation.Herein,we summarize current research progress of MSC-Exos for skin wound treatment,with an emphasis on the biological effects of these nanovesicles,the repair mechanisms,and future challenges in clinical translation.
基金sponsored by the National Natural Science Foundation of China(Grant No.32171351 and 82000969)the“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002)+1 种基金Post-Doctor Research Project,West China Hospital,Sichuan University(Grant No.2021HXBH005)Key Research and Development Program of Sichuan Province(Grant No.2021YFS0216)。
文摘Injection laryngoplasty with biomaterials is an effective technique to treat glottic insufficiency.However,the inadequate durability,deficient pro-secretion of extracellular matrix(ECM)and poor functional preservation of current biomaterials have yielded an unsatisfactory therapeutic effect.Herein,a self-fusing bioactive hydrogel comprising modified carboxymethyl chitosan and sodium alginate is developed through a dual-crosslinking mechanism(photo-triggered and dynamic covalent bonds).Owing to its characteristic networks,the synergistic effect of the hydrogel for vocal folds(VFs)vibration and phonation is adequately demonstrated.Notably,owing to its inherent bioactivity of polysaccharides,the hydrogel could significantly enhance the secretion of major components(type I/III collagen and elastin)in the lamina propria of the VFs both in vivo and in vitro.In a rabbit model for glottic insufficiency,the optimized hydrogel(C1A1)has demonstrated a durability far superior to that of the commercially made hyaluronic acid(HA)Gel.More importantly,owing to the ECM-inducing bioactivity,the physiological functions of the VFs treated with the C1A1 hydrogel also outperformed that of the HA Gel,and were similar to those of the normal VFs.Taken together,through a simple-yet-effective strategy,the novel hydrogel has demonstrated outstanding durability,ECM-inducing bioactivity and physiological function preservation,therefore has an appealing clinical value for treating glottic insufficiency.
基金supported by National Natural Science Foundation of China(Grant No.31771065)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002).
文摘As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount of research on the topic,the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored,though many aspects still remain unclear.In this review,we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin,bone and articular cartilage repair.In addition to the identification procedure of USCs,we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs.Potential concerns and perspectives have also been summarized.
基金supported by the National Natural Science Foundation of China(Grant No.32171351,31771065)National Key Research and Development Program of China(Grant No.2017YFC1104702)the“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002).
文摘The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes.Biomaterials such as submucosa of small intestine(SIS)have been widely used as patches for bladder repair,but the outcomes are not fully satisfactory.To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization.In this study,we have developed an anti-CD29 antibody-conjugated SIS scaffold(AC-SIS)which is capable of specifically capturing urine-derived stem cells(USCs)in situ for tissue repair and regeneration.The scaffold has exhibited effective capture capacity and sound biocompatibility.In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration.The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.
基金supported by the National Natural Science Foundation of China(No.81672209,81871769,82272550)the Chongqing Science and Technology Bureau(China)(No.cstc2021jcyj-bshX0214).
文摘Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.
基金supported by the National Key R&D Program of China(Grant No.2017YFC1104702)National Natural Science Foundation of China(Grant No.31771065)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002).
文摘Approximately 25%of patients with congenital heart disease require implantation of patches to repair.However,most of the currently available patches are made of inert materials with unmatched electrical conductivity and mechanical properties,which may lead to an increased risk for arrhythmia and heart failure.In this study,we have developed a novel Polyurethane/Small intestinal submucosa patch(PSP)with mechanical and electrical properties similar to those of the native myocardial tissue,and assessed its feasibility for the reconstruction of right ventricular outflow tract.A right ventricular outflow tract reconstruction model was constructed in 40 rabbits.Compared with commercially available bovine pericardium patch,the PSP patch has shown better histocompatibility and biodegradability,in addition with significantly improved cardiac function.To tackle the significant fibrosis and relatively poor vascularization during tissue remodeling,we have further developed a bioactive patch by incorporating the PSP composites with urine-derived stem cells(USCs)which were pretreated with hypoxia.The results showed that the hypoxia-pretreated bioactive patch could significantly inhibit fibrosis and promote vascularization and muscularization,resulting in better right heart function.Our findings suggested that the PSP patch combined with hypoxia-pretreated USCs may provide a better strategy for the treatment of congenital heart disease.
基金supported by the grants from National Natural Science Foundation of China(grant numbers:32171349,31600783,31870968)Science and Technology Plan of Sichuan Province(grant number:2018SZ0044).
文摘Developing highly bioactive scaffold materials to promote stem cell migration,proliferation and tissue-specific differentiation is a crucial requirement in current tissue engineering and regenerative medicine.Our previous work has demonstrated that the decellularized tendon slices(DTSs)are able to promote stem cell proliferation and tenogenic differentiation in vitro and show certain pro-regenerative capacity for rotator cuff tendon regeneration in vivo.In this study,we present a strategy to further improve the bioactivity of the DTSs for constructing a novel highly bioactive tendon-regenerative scaffold by surface modification of tendon-specific stem cell-derived extracellular matrix(tECM),which is expected to greatly enhance the capacity of scaffold material in regulating stem cell behavior,including migration,proliferation and tenogenic differentiation.We prove that the modification of tECM could change the highly aligned surface topographical cues of the DTSs,retain the surface stiffness of the DTSs and significantly increase the content of multiple ECM components in the tECM-DTSs.As a result,the tECM-DTSs dramatically enhance the migration,proliferation as well as tenogenic differentiation of rat bone marrow-derived stem cells compared with the DTSs.Collectively,this strategy would provide a new way for constructing ECMbased biomaterials with enhanced bioactivity for in situ tendon regeneration applications.
基金sponsored by the National Natural Science Foundation of China(31771065)Sichuan Science and Technology Program(2019JDRC0020)the“1.3.5 Program for Disciplines of Excellence,”West China Hospital,Sichuan University(ZYJC18002)。
文摘Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine.Nevertheless,limited yield has restrained full explication of their functions and clinical applications.To address this,various attempts have been made to explore the up-and down-stream manipulations in a bid to increase the production of exosomes.This review has recapitulated factors which may influence the yield of stem cell-derived exosomes,including selection and culture of stem cells,isolation and preservation of the exosomes,and development of artificial exosomes.
基金supported by grants from the National Key R&D Program of China(2021YFA1100600 to S.S.)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.,D-11 to X.K.)+5 种基金the Pearl River Talent Recruitment Program(2019ZT08Y485)the National Science and Technology Major Project of the Ministry of Science and Technology of China(2018ZX10302207-001-002)the Sun Yat-sen University Young Teacher Key Cultivation Project(18ykzd05 to X.K.)the Natural Science Foundation of Guangdong(2016A030313262 to X.M.)the National Natural Science Foundation of China(82170924 to X.K.,81700928 to L.M.)the Youth Teacher Training Project of Sun Yat-sen University(17ykpy71 to L.M.).
文摘Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.
基金supported by the National Natural Science Foundation of China(Grant No.32171351)the“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002)China Postdoctoral Science Foundation(2022M722277).
文摘Endoscopic submucosal dissection (ESD) for gastrointestinal tumors and premalignant lesions needs submucosal fluid cushion (SFC) for mucosal uplift before dissection, and wound care including wound closure and rapid healing postoperatively. Current SFC materials as well as materials and/or methods for post-ESD wound care have single treatment effect and hold corresponding drawbacks, such as easy dispersion, short duration, weak hemostasis and insufficient repair function. Thus, designing materials that can serve as both SFC materials and wound care is highly desired, and remains a challenge. Herein, we report a two-component in-situ hydrogel prepared from maleimide-based oxidized sodium alginate and sulfhydryl carboxymethyl-chitosan, which gelated mainly based on "click" chemistry and Schiff base reaction. The hydrogels showed short gelation time, outstanding tissue adhesion, favorable hemostatic properties, and good biocompatibility. A rat subcutaneous ultrasound model confirmed the ability of suitable mucosal uplift height and durable maintenance time of AM solution. The in vivo/in vitro rabbit liver hemorrhage model demonstrated the effects of hydrogel in rapid hemostasis and prevention of delayed bleeding. The canine esophageal ESD model corroborated that the in-situ hydrogel provided good mucosal uplift and wound closure effects, and significantly accelerated wound healing with accelerating re-epithelization and ECM remodeling post-ESD. The two-component in-situ hydrogels exhibited great potential in gastrointestinal tract ESD.
基金supported by the National Natural Science Foundation of China(No.81672209)Chongqing Science and Technology Bureau(No.cstc2020jcyj-msxmX0175),ChinaChongqing Human Resources and Social Security Bureau(No.2018-389),China.
文摘Progranulin(PGRN)is a multifunctional growth factor involved in many physiolog-ical processes and disease states.The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis(OA)led us to investi-gate the role of PGRN in the regulation of chondrocyte autophagy.PGRN knockout chondro-cytes exhibited a deficient autophagic response with limited induction following rapamycin,serum starvation,and IL-1b-induced autophagy.PGRN-mediated anabolism and suppression of IL-1b-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor.Mechanistically,during the process of OA,PGRN and the ATG5eATG12 conjugate form a protein complex;PGRN regulates autophagy in chondrocytes and OA through,at least partially,the interactions between PGRN and the ATG5eATG12 conjugate.Furthermore,the ATG5eATG12 conjugate is critical for cell proliferation and apoptosis.Knockdown or knockout of ATG5 reduces the expression of ATG5eATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism.Overexpression of PGRN partially reversed this effect.In brief,the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA.Such studies provide new insights into the pathogen-esis of OA and PGRN-associated autophagy in chondrocyte homeostasis.
基金the National Natural Science Foundation of China,No.30973155
文摘In the present study,tissue blocks were randomly sampled from the entire hippocampus of 6-week-old Long-Evans rats.Isotropic,uniform and random sections,60 nm thick,were prepared by isector.Fifteen fields of view were randomly selected for each section and photographed using a transmission electron microscope.The mean internal and external diameters of the myelin sheaths were obtained by measuring the longest profile diameter perpendicular to its longest axis.The inner and outer perimeters of the myelin sheaths were estimated using the equidistant parallel test lines.The thickness of the myelin sheaths was estimated by direct orthogonal measurements in uniform,random locations.These stereological methods should permit an unbiased quantitative assessment of changes in the myelin sheaths of myelinated fibers in the hippocam-pus.
基金supported by the National Natural Science Foundation of China(Grant No.81873103)the Foundation and Frontier Research Project of Chongqing Science and Technology Commission(Grant No.cstc2014jcyjA10001).
文摘Chemotherapy may cause cellular oxidative stress to bone marrow.Oxidative damage of bone marrow hematopoietic microenvironment is closely related to chronic myelosuppression after chemotherapeutic treatment.Angelica sinensis polysaccharides(ASP)are major effective ingredients of traditional Chinese medicine Angelica with multi-target anti-oxidative stress features.In the current study,we investigated the protective roles and mechanisms of ASP on chemotherapy-induced bone marrow stromal cell(BMSC)damage.The human bone marrow stromal cell line HS-5 cells were divided into control group,5-FU group,5-FU+ASP group,and 5-FU+LiCl group to investigate the mechanism of ASP to alleviate 5-FU-induced BMSC proliferation inhibition.The results showed that 5-FU inhibits the growth of HS-5 cells in a time and dose-dependent manner;however,ASP partially counteracted the 5-FU-induced decrease in cell viability,whereas Wnt signaling inhibitor Dkk1 antagonized the effect of ASP on HS-5 cells.ASP reversed the decrease in total cytoplasmicβ-catenin,p-GSK-3β,and CyclinD1 following 5-FU treatment and modulated nuclear expression ofβ-catenin,Lef-1,and C-myc proteins.Furthermore,ASP also enhanced the antioxidant capacity of cells and reduced 5-FU-induced oxidative stress,attenuated FoxO1 expression,thus weakened its downstream apoptosis-related proteins and G0/G1 checkpoint-associated p27^(Kip1) expression to alleviate 5-FU-induced apoptosis and to promote cell cycle progression.All the results above suggest that the protective role of ASP in 5-FU-treated BMSCs proliferation for the chemotherapy may be related to its activating Wnt/β-catenin signaling and keeping homeostasis betweenβ-catenin and FoxO1 under oxidative stress.The study provides a potential therapeutic strategy for alleviating chemotherapeutic damage on BMSCs.
