The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to ...The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to treat breast cancer via accurate tumor elimination,on-demand adipose tissue regeneration and effective infection inhibition.The hydrogel consisted of thiol groups ended polyethylene glycol(SH-PEG-SH)and doxorubicin encapsulated mesoporous silica nanocarriers(DOX@MSNs)double crosslinked hyaluronic acid(HA)after loading of antibacterial peptides(AP)and adipose-derived stem cells(ADSCs).A pH-cleavable unsaturated amide bond was pre-introduced between MSNs and HA frame to perform the tumor-specific acidic environment dependent DOX@MSNs release,meanwhile an esterase degradable glyceryl dimethacrylate cap was grafted on MSNs,which contributed to the selective chemotherapy in tumor cells with over-expressed esterase.The bond cleavage between MSNs and HA would also cause the swelling of the hydrogel,which not only provide sufficient space for the growth of ADSCs,but allows the hydrogel to fully fill the irregular defects generated by surgery and residual tumor atrophy,resulting in the on-demand regeneration of adipose tissue.Moreover,the sustained release of AP could be simultaneously triggered along with the size change of hydrogel,which further avoided bacterial infection to promote tissue regeneration.展开更多
The issue of plastic pollutants has become a growing concern.Both microplastics(MPs)(particle size<5 mm)and nanoplastics(NPs)(particle size<1μm)can cause DNA damage,cytotoxicity,and oxidative stress in various ...The issue of plastic pollutants has become a growing concern.Both microplastics(MPs)(particle size<5 mm)and nanoplastics(NPs)(particle size<1μm)can cause DNA damage,cytotoxicity,and oxidative stress in various organisms.The primary known impacts of microplastic/nanoplastic are observed in the liver and respiratory system,leading to hepatotoxicity and chronic obstructive pulmonary disease.Although research on the effects of MPs and NPs on diabetes is still in its early stages,there are potential concerns.This editorial highlights the risk to diabetics from co-exposure to contaminants and MPs/NPs,supported by evidence from animal studies and the various chemical compositions of MPs/NPs.展开更多
Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandin...Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive.Here,we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell(MSC)function and regeneration.Interestingly,replenishment of cell aggregates-derived extracellular vesicles(CA-EVs)rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5.Importantly,in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice,suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration.Collectively,our findings provide insights into Golgi regulation in stem cell senescence and bone aging,which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.展开更多
BACKGROUND The risk factors and prediction models for diabetic foot(DF)remain incompletely understood,with several potential factors still requiring in-depth investigations.AIM To identify risk factors for new-onset D...BACKGROUND The risk factors and prediction models for diabetic foot(DF)remain incompletely understood,with several potential factors still requiring in-depth investigations.AIM To identify risk factors for new-onset DF and develop a robust prediction model for hospitalized patients with type 2 diabetes.METHODS We included 6301 hospitalized patients with type 2 diabetes from January 2016 to December 2021.A univariate Cox model and least absolute shrinkage and selection operator analyses were applied to select the appropriate predictors.Nonlinear associations between continuous variables and the risk of DF were explored using restricted cubic spline functions.The Cox model was further employed to evaluate the impact of risk factors on DF.The area under the curve(AUC)was measured to evaluate the accuracy of the prediction model.RESULTS Seventy-five diabetic inpatients experienced DF.The incidence density of DF was 4.5/1000 person-years.A long duration of diabetes,lower extremity arterial disease,lower serum albumin,fasting plasma glucose(FPG),and diabetic nephropathy were independently associated with DF.Among these risk factors,the serum albumin concentration was inversely associated with DF,with a hazard ratio(HR)and 95%confidence interval(CI)of 0.91(0.88-0.95)(P<0.001).Additionally,a U-shaped nonlinear relationship was observed between the FPG level and DF.After adjusting for other variables,the HRs and 95%CI for FPG<4.4 mmol/L and≥7.0 mmol/L were 3.99(1.55-10.25)(P=0.004)and 3.12(1.66-5.87)(P<0.001),respectively,which was greater than the mid-range level(4.4-6.9 mmol/L).The AUC for predicting DF over 3 years was 0.797.CONCLUSION FPG demonstrated a U-shaped relationship with DF.Serum albumin levels were negatively associated with DF.The prediction nomogram model of DF showed good discrimination ability using diabetes duration,lower extremity arterial disease,serum albumin,FPG,and diabetic nephropathy(Clinicaltrial.gov NCT05519163).展开更多
BACKGROUND The current case report describes successful phacoemulsification with the aid of perioperative topical ascorbic acid(AA) in two patients with corneal endothelial disorders to prevent postoperative corneal e...BACKGROUND The current case report describes successful phacoemulsification with the aid of perioperative topical ascorbic acid(AA) in two patients with corneal endothelial disorders to prevent postoperative corneal endothelial decompensation.CASE SUMMARY Two eyes of two patients underwent phacoemulsification with pre-existing corneal endothelial disorders including Fuchs corneal endothelial dystrophy(Patient 1) and endotheliitis(Patient 2). Topical AA was applied to both patients at least one month before and after with a frequency of four times per day. After the surgery, both eyes improved best-corrected visual acuity(BCVA) and there was limited human corneal endothelial cell loss without signs of corneal endothelial decompensation, such as deteriorated BCVA or persistent corneal edema during the follow-up of at least two years.CONCLUSION Perioperative administration of topical AA may be an alternative therapy to the triple procedure in patients expecting to undergo cataract surgery.展开更多
Objective Anastomotic leakage(AL)is one of the serious complications after anterior resection for rectal cancer.Defunctioning stoma(DS)is one of the most widely used approaches to prevent it;however,the effect of DS o...Objective Anastomotic leakage(AL)is one of the serious complications after anterior resection for rectal cancer.Defunctioning stoma(DS)is one of the most widely used approaches to prevent it;however,the effect of DS on the occurrence of AL remains controversial.This study aimed to investigate risk factors of AL and assess the effect of DS after anterior resection for rectal cancer patients.Methods A retrospective analysis was conducted for the data of 1840 patients who underwent anterior resection for rectal cancer from January 2014 to December 2019.Results The results showed the overall AL incidence was 7.5%.Multivariate analyses revealed that males[odds ratio(OR)1.562]and T3–T4 stage(OR 1.729)were independent risk factors for all patients.After propensity score matching analysis,the AL incidence was 14.1%in the group with no DS and 6.4%in the DS group(P<0.001).The clinical AL(grade B+grade C)incidence was 12.4%in no DS group and 4.6%in the DS group(P<0.001).Conclusion The study suggested that males and T3–T4 stage were independent risk factors of AL.In addition,DS could reduce the rate of symptomatic AL.展开更多
Poor healing of cutaneous wounds is a common medical problem in the field of traumatology.Due to the intricate pathophysiological processes of wound healing,the use of conventional treatment methods,such as chemical m...Poor healing of cutaneous wounds is a common medical problem in the field of traumatology.Due to the intricate pathophysiological processes of wound healing,the use of conventional treatment methods,such as chemical molecule drugs and traditional dressings,have been unable to achieve satisfactory outcomes.Within recent years,explicit evidence suggests that mesenchymal stem cells(MSCs)have great therapeutic potentials on skin wound healing and regeneration.However,the direct application of MSCs still faces many challenges and difficulties.Intriguingly,exosomes as cell-secreted granular vesicles with a lipid bilayer membrane structure and containing specific components from the source cells may emerge to be excellent substitutes for MSCs.Exosomes derived from MSCs(MSC-exosomes)have been demonstrated to be beneficial for cutaneous wound healing and accelerate the process through a variety of mechanisms.These mechanisms include alleviating inflammation,promoting vascularization,and promoting proliferation and migration of epithelial cells and fibroblasts.Therefore,the application of MSC-exosomes may be a promising alternative to cell therapy in the treatment of cutaneous wounds and could promote wound healing through multiple mechanisms simultaneously.This review will provide an overview of the role and the mechanisms of MSC-derived exosomes in cutaneous wound healing,and elaborate the potentials and future perspectives of MSC-exosomes application in clinical practice.展开更多
Objective:To investigate the biological effects of the Mucuna pruriens(M.pruriens)seed extracts that lacked of L-DOPA,which was formerly reported as the active ingredient,on erectile dysfunction(ED)both in vitro and i...Objective:To investigate the biological effects of the Mucuna pruriens(M.pruriens)seed extracts that lacked of L-DOPA,which was formerly reported as the active ingredient,on erectile dysfunction(ED)both in vitro and in vivo.Methods:Seed of M.pruriens plant that cultivated in Mae Taeng District,Chiang Mai Province,Thailand,was collected.Component of its seeds were extracted and isolated into 2 fractions using methanol,polar and nonpolar.Each fraction was investigated for phytochemicals using GC/MS and was screened for biological activity In vitro using three different cell lines.The most biological active fraction was used to treat to both steptozotocin(STZ)-induced diabetes mellitus-erectile dysfunction(DM-ED)male wistar rats and normal rats(n=6 per groups)to compare the effect on sexual behaviour parameters,including number of intromission,mounting and ejaculation,with that of rats given Sildenafil by individually pairing with their female counterparts.Penile tissues and serums were collected to determine histological structure,related gene expression and biomolecules.Results:The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols,whereas the nonpolar fraction consisted of lipid derivatives.L-DOPA was not detected in either of the extracts.The polar fraction was able to up-regulate the expression of ED-related genes including e NOS and n NOS in vitro which subsequently promotes NO production and maintains intracellular cG MP levels.When administrated to DM-ED rats,the polar extract significantly improved all sexual behaviour parameters in DM-ED rats compare to untreated group(18.3±1.8 to 10.8±2.9 for intromission,9.8±2.2 to 5.7±1.3 for mounting,and 1.8±0.6 to 0.2±0.4 for ejaculation).That effect might due to the ability of the extract to stimulate the expression of eN OS and nN OS which results in NO production and subsequently maintains cG MP levels in penile tissue.Moreover,this extract may also prevent penile tissue deterioration due to diabetes.Conclusions:The polar extract of M.pruriens seed can be used for ED therapy,especially in patients with metabolic diseases including diabetes.The action of the extract might be due to catechol and its derivatives and polyphenols.展开更多
Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines rema...Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines remains elusive.Here,we reveal that even under physiological conditions,MSCs produce and release a low level of tumor necrosis factor alpha(TNFα),which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling.Furthermore,TNFαcritically maintains MSC function in vivo during bone homeostasis.Mechanistically,we unexpectedly discovered that physiological levels of TNFαsafeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFαbinds to mammalian target of rapamycin(mTOR)complex 2 and restricts mTOR signaling.Importantly,inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFαdeficiency and mechanical unloading.Collectively,these findings unravel the physiological framework of the dynamic TNFαshuttlebased mTOR equilibrium that governs MSC and bone homeostasis.展开更多
Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity...Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens.Omiganan,an antimicrobial peptide,has shown promise for neutralizing endotoxins and eliminating diverse pathogens.However,its clinical application is hindered by safety and stability concerns.Herein,we present a nanoscale drug delivery system(Omi-hyd-Dex@HA NPs)that selectively targets infectious microenvironments(IMEs)and responds to specific stimuli for efficient intervention in sepsis.The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid(HA).The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes,but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase.The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation.In multiple tissue infection and sepsis animal models,Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction,thereby preventing subsequent fatal complications and significantly improving survival outcomes.The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.展开更多
In the context of the circular economy,the huge amounts of biomass waste should be converted into value-added materials and energy to diminish pollution,atmospheric CO_(2)levels and costly waste disposal.Biological im...In the context of the circular economy,the huge amounts of biomass waste should be converted into value-added materials and energy to diminish pollution,atmospheric CO_(2)levels and costly waste disposal.Biological imaging usually uses expensive and toxic chemicals e.g.,organic dyes,semiconductor quantum dots,calling for safer,greener,cheaper fluorescent probes for biological imaging in vitro and in vivo.In these regards,carbon quantum dots(CQDs)-based fluorescent probes using biomass waste as a precursor may have much higher potential.Here we transformed the biomass waste of peach leaves into value-added fluorescent CQDs through a low-cost and green one-step hydrothermal process.The obtained CQDs show excitation-dependent photoluminescence properties with a fluorescence lifetime of 5.96 ns and a quantum yield of 7.71%without any passivation.In addition,the CQDs have a fine size of 1.9 nm with good hydrophilicity and high fluorescent stability over pH 4.0-11.0 range.Fluorescence imaging of in vitro cell cultures and in vivo with zebrafish show that CQDs possess ultra-low toxicity and remarkable performance for biological imaging.Even when CQDs present at a concentration as high as500μg/m L,the organism can still maintain more than 90%activity both in vitro and in vivo,and present bright fluorescence.The cheaper,greener,ultra-low toxicity CQDs developed in this work is a potential candidate for biological imaging in vitro and in vivo.展开更多
BACKGROUND Streptococcus mitis(S.mitis)is an opportunistic pathogen that can lead to severe ocular infections.In previous reports,penetrating keratoplasty(PK)was usually adopted for the treatment of persistent corneal...BACKGROUND Streptococcus mitis(S.mitis)is an opportunistic pathogen that can lead to severe ocular infections.In previous reports,penetrating keratoplasty(PK)was usually adopted for the treatment of persistent corneal ulcers.This report describes an unusual case of nonhealing descemetocele caused by S.mitis treated by antibiotics plus amniotic membrane transplantation(AMT).CASE SUMMARY A 63-year-old woman presented with a right persistent corneal ulcer that she had suffered from for the past 9 mo.The culture of a corneal scraping yielded S.mitis.The right eye descemetocele decreased in diameter from 3 to 0.8 mm after the continuous administration of topical vancomycin and ceftriaxone for 2 wk.Due to the slow healing,AMT was performed.Her corneal erosion healed and gradually became clear.Her visual acuity recovered from initially counting fingers to 100/200 at the last follow-up,67 mo after AMT.CONCLUSION Antibiotics plus AMT may be an effective alternative treatment other than PK to promote epithelializationand to reduce inflammation in the corneas complicated by S. mitis keratitis.展开更多
Dental stem cells can differentiate into different types of cells.Dental pulp stem cells,stem cells from human exfoliated deciduous teeth,periodontal ligament stem cells,stem cells from apical papilla,and dental folli...Dental stem cells can differentiate into different types of cells.Dental pulp stem cells,stem cells from human exfoliated deciduous teeth,periodontal ligament stem cells,stem cells from apical papilla,and dental follicle progenitor cells are five different types of dental stem cells that have been identified during different stages of tooth development.The availability of dental stem cells from discarded or removed teeth makes them promising candidates for tissue engineering.In recent years,three-dimensional(3D)tissue scaffolds have been used to reconstruct and restore different anatomical defects.With rapid advances in 3D tissue engineering,dental stem cells have been used in the regeneration of 3D engineered tissue.This review presents an overview of different types of dental stem cells used in 3D tissue regeneration,which are currently the most common type of stem cells used to treat human tissue conditions.展开更多
Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the e...Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the excellent selectivity of AS1411 aptamer to targeted nucleolin-overexpressed cells, we used a fluorescent probe with a pH-sensitive function to label the AS1411 aptamer modified with azide by click-reaction. The spectral characteristics of fluorophore naphthalimide has a good pH dependence. By this way, nucleolin-overexpressed cell could be discriminated from normal cell. Further, this strategy could also discriminate the breast cancer tissue from the adjacent benign tissue in formalin-fixed and parrffin-embedded（FFPE） tissue specimens. It is considered that our method has the potential to be applied in medical detection.展开更多
Tissue engineering strategies hold promise for constructing biomimetic tracheal substitutes to repair circum-ferential tracheal defects.However,current strategies for constructing off-the-shelf cartilage analogs for a...Tissue engineering strategies hold promise for constructing biomimetic tracheal substitutes to repair circum-ferential tracheal defects.However,current strategies for constructing off-the-shelf cartilage analogs for artificial trachea grafts face challenges of chondrocyte scarcity and inadequate culture strategies,which require extensive cell expansion and prolonged in vitro culture to generate robust neo-cartilage.To address these issues,we developed a nanofiber-hydrogel composite with superior mechanical performance by incorporating fragment oxidized bacterial cellulose(BC)nanofibers into a gelatin methacryloyl(GelMA)hydrogel network.Additionally,a biomaterial system was developed based on this composite,featuring dual-release functionality of fibroblast growth factor(FGF)and transforming growth factor beta(TGF-β)to facilitate step-wise maturation of neo-cartilage tissue.This process includes early-stage proliferation followed by second-stage extracellular matrix(ECM)deposition,driving the transition from proliferation to chondrogenesis.By encapsulating chondrocytes within the biomaterial system,mature neo-cartilage tissues with typical cartilage lacunae structures and abun-dant homogeneous cartilage-specific ECM deposition were successfully regenerated in vitro and in vivo.Furthermore,with a tailor-made growth factor-releasing strategy,the biomaterial system with low cell seeding density achieved biochemically and biomechanically functional neo-cartilage tissue regeneration,comparable to that achieved with high cell seeding density in the nanofiber-hydrogel composite.Based on the current biomaterial system,mature and functional cartilage-ring analogs were successfully constructed and applied to repair tracheal defects.Overall,the biomaterial system developed in this study provides a promising strategy for engineering transplantable,high-quality cartilage substitutes,with translational potential for artificial trachea construction.展开更多
Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In...Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In regenerative medicine,harnessing developmental principles for tissue repair offers promising therapeutic potential.Of particular interest is the condensation of progenitor cells,an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration.However,the precise cellular coordination mechanisms during condensation and regeneration remain elusive.Here,taking the tooth as a model organ,we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla,revealing a distinct Platelet-derived growth factor receptor alpha(PDGFRA)mesenchymal stem/stromal cell(MSC)population with remarkable odontogenic potential.Interestingly,a reciprocal paracrine interaction between PDGFRA^(+)dental follicle stem cells(DFSCs)and CD31^(+)Endomucin^(+)endothelial cells(ECs)was mediated by Vascular endothelial growth factor A(VEGFA)and Platelet-derived growth factor subunit BB(PDGFBB).This crosstalk not only maintains the functionality of PDGFRA^(+)DFSCs but also drives specialized angiogenesis.In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair.Collectively,our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis.These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.展开更多
In modern medicine,bone and dental loss and defects are common and widespread morbidities,for which regenerative therapy has shown great promise.Mesenchymal stem cells,obtained from various sources and playing an esse...In modern medicine,bone and dental loss and defects are common and widespread morbidities,for which regenerative therapy has shown great promise.Mesenchymal stem cells,obtained from various sources and playing an essential role in organ development and postnatal repair,have exhibited enormous potential for regenerating bone and dental tissue.Currently,mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering.Nevertheless,the efficacy of MSCbased regeneration is not always fulfilled,especially in diseased microenvironments.Specifically,the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs,both as donors and recipients.Accordingly,approaches targeting a diseased microenvironment have been established,including improving the diseased niche to restore endogenous MSCs,enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies.Moreover,the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy.In this review,we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment,emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.展开更多
The development of cell biology, molecular biology, and material science, has been propelling biomimic tissue-engineered skins to become more sophisticated in scientificity and more simplified in practicality. In orde...The development of cell biology, molecular biology, and material science, has been propelling biomimic tissue-engineered skins to become more sophisticated in scientificity and more simplified in practicality. In order to improve the safety, durability, elasticity, biocompatibility, and clinical efficacy of tissue-engineered skin, several powerful seed cells have already found their application in wound repair, and a variety of bioactive scaffolds have been discovered to influence cell fate in epidermogenesis. These exuberant interests provide insights into advanced construction strategies for complex skin mimics. Based on these exciting developments, a complete full-thickness tissue-engineered skin is likely to be generated.展开更多
Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where...Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A(p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells(MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/-mice by improving the function of endogenous MSCs.These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.展开更多
The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or ...The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain,chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells(BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl+/- mice and BMSC-specific(Prrx1-alpl-/-) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca2+ influx, which it achieves by regulating L-type Ca2+ channel trafficking via binding to the α2δsubunits to regulate the internalization of the L-type Ca2+ channel. Decreased Ca2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca2+ flux through L-type Ca2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.展开更多
基金the National High Level Talents Special Support Plan(X.C.)the“Young Talent Support Plan”of Xi'an Jiaotong University(X.C.)+2 种基金the Natural Science Foundation of Shaanxi Province(No.2022JZ-48 to X.C.)the National Natural Science Foundation of China(No.82272141 to X.C.)the Shaanxi Provincial Key Research and Development Plan Project(No.2023-JC-QN-0260 to X.Q.).
文摘The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to treat breast cancer via accurate tumor elimination,on-demand adipose tissue regeneration and effective infection inhibition.The hydrogel consisted of thiol groups ended polyethylene glycol(SH-PEG-SH)and doxorubicin encapsulated mesoporous silica nanocarriers(DOX@MSNs)double crosslinked hyaluronic acid(HA)after loading of antibacterial peptides(AP)and adipose-derived stem cells(ADSCs).A pH-cleavable unsaturated amide bond was pre-introduced between MSNs and HA frame to perform the tumor-specific acidic environment dependent DOX@MSNs release,meanwhile an esterase degradable glyceryl dimethacrylate cap was grafted on MSNs,which contributed to the selective chemotherapy in tumor cells with over-expressed esterase.The bond cleavage between MSNs and HA would also cause the swelling of the hydrogel,which not only provide sufficient space for the growth of ADSCs,but allows the hydrogel to fully fill the irregular defects generated by surgery and residual tumor atrophy,resulting in the on-demand regeneration of adipose tissue.Moreover,the sustained release of AP could be simultaneously triggered along with the size change of hydrogel,which further avoided bacterial infection to promote tissue regeneration.
基金Supported by Research grant from Chang Gung Memorial Hospital,Linkou,Taiwan,No.CMRPG3N0622.
文摘The issue of plastic pollutants has become a growing concern.Both microplastics(MPs)(particle size<5 mm)and nanoplastics(NPs)(particle size<1μm)can cause DNA damage,cytotoxicity,and oxidative stress in various organisms.The primary known impacts of microplastic/nanoplastic are observed in the liver and respiratory system,leading to hepatotoxicity and chronic obstructive pulmonary disease.Although research on the effects of MPs and NPs on diabetes is still in its early stages,there are potential concerns.This editorial highlights the risk to diabetics from co-exposure to contaminants and MPs/NPs,supported by evidence from animal studies and the various chemical compositions of MPs/NPs.
基金supported by grants from the National Natural Science Foundation of China(81930025,82201013,82371020,82370949,82100992)the Young Science and Technology Rising Star Project of Shaanxi Province(2023KJXX-027)the China Postdoctoral Science Foundation(BX20230485).
文摘Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive.Here,we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell(MSC)function and regeneration.Interestingly,replenishment of cell aggregates-derived extracellular vesicles(CA-EVs)rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5.Importantly,in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice,suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration.Collectively,our findings provide insights into Golgi regulation in stem cell senescence and bone aging,which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.
基金Supported by National Natural Science Foundation of China,No.81972947Academic Promotion Programme of Shandong First Medical University,No.2019LJ005.
文摘BACKGROUND The risk factors and prediction models for diabetic foot(DF)remain incompletely understood,with several potential factors still requiring in-depth investigations.AIM To identify risk factors for new-onset DF and develop a robust prediction model for hospitalized patients with type 2 diabetes.METHODS We included 6301 hospitalized patients with type 2 diabetes from January 2016 to December 2021.A univariate Cox model and least absolute shrinkage and selection operator analyses were applied to select the appropriate predictors.Nonlinear associations between continuous variables and the risk of DF were explored using restricted cubic spline functions.The Cox model was further employed to evaluate the impact of risk factors on DF.The area under the curve(AUC)was measured to evaluate the accuracy of the prediction model.RESULTS Seventy-five diabetic inpatients experienced DF.The incidence density of DF was 4.5/1000 person-years.A long duration of diabetes,lower extremity arterial disease,lower serum albumin,fasting plasma glucose(FPG),and diabetic nephropathy were independently associated with DF.Among these risk factors,the serum albumin concentration was inversely associated with DF,with a hazard ratio(HR)and 95%confidence interval(CI)of 0.91(0.88-0.95)(P<0.001).Additionally,a U-shaped nonlinear relationship was observed between the FPG level and DF.After adjusting for other variables,the HRs and 95%CI for FPG<4.4 mmol/L and≥7.0 mmol/L were 3.99(1.55-10.25)(P=0.004)and 3.12(1.66-5.87)(P<0.001),respectively,which was greater than the mid-range level(4.4-6.9 mmol/L).The AUC for predicting DF over 3 years was 0.797.CONCLUSION FPG demonstrated a U-shaped relationship with DF.Serum albumin levels were negatively associated with DF.The prediction nomogram model of DF showed good discrimination ability using diabetes duration,lower extremity arterial disease,serum albumin,FPG,and diabetic nephropathy(Clinicaltrial.gov NCT05519163).
基金Supported by the Chang Gung Memorial Hospital,No.CMRPG3F1471~2 and No.CMRPG3G0031~3the Ministry of Science and Technology No.MOST106-2314-B-182A-042-34 and No.MOST 107-2314-B-182A-088-MY3
文摘BACKGROUND The current case report describes successful phacoemulsification with the aid of perioperative topical ascorbic acid(AA) in two patients with corneal endothelial disorders to prevent postoperative corneal endothelial decompensation.CASE SUMMARY Two eyes of two patients underwent phacoemulsification with pre-existing corneal endothelial disorders including Fuchs corneal endothelial dystrophy(Patient 1) and endotheliitis(Patient 2). Topical AA was applied to both patients at least one month before and after with a frequency of four times per day. After the surgery, both eyes improved best-corrected visual acuity(BCVA) and there was limited human corneal endothelial cell loss without signs of corneal endothelial decompensation, such as deteriorated BCVA or persistent corneal edema during the follow-up of at least two years.CONCLUSION Perioperative administration of topical AA may be an alternative therapy to the triple procedure in patients expecting to undergo cataract surgery.
基金supported by grants from the National Natural Science Foundation of China(No.81974382)the Major Scientific and Technological Innovation Projects in Hubei Province(No.2018ACA136)the Innovative Team for Human Major Diseases Program,Tongji Medical College,Huazhong University of Science and Technology.
文摘Objective Anastomotic leakage(AL)is one of the serious complications after anterior resection for rectal cancer.Defunctioning stoma(DS)is one of the most widely used approaches to prevent it;however,the effect of DS on the occurrence of AL remains controversial.This study aimed to investigate risk factors of AL and assess the effect of DS after anterior resection for rectal cancer patients.Methods A retrospective analysis was conducted for the data of 1840 patients who underwent anterior resection for rectal cancer from January 2014 to December 2019.Results The results showed the overall AL incidence was 7.5%.Multivariate analyses revealed that males[odds ratio(OR)1.562]and T3–T4 stage(OR 1.729)were independent risk factors for all patients.After propensity score matching analysis,the AL incidence was 14.1%in the group with no DS and 6.4%in the DS group(P<0.001).The clinical AL(grade B+grade C)incidence was 12.4%in no DS group and 4.6%in the DS group(P<0.001).Conclusion The study suggested that males and T3–T4 stage were independent risk factors of AL.In addition,DS could reduce the rate of symptomatic AL.
基金Supported by National Natural Science Foundation of China,No. 32000974, No. 82170988, and No. 81930025
文摘Poor healing of cutaneous wounds is a common medical problem in the field of traumatology.Due to the intricate pathophysiological processes of wound healing,the use of conventional treatment methods,such as chemical molecule drugs and traditional dressings,have been unable to achieve satisfactory outcomes.Within recent years,explicit evidence suggests that mesenchymal stem cells(MSCs)have great therapeutic potentials on skin wound healing and regeneration.However,the direct application of MSCs still faces many challenges and difficulties.Intriguingly,exosomes as cell-secreted granular vesicles with a lipid bilayer membrane structure and containing specific components from the source cells may emerge to be excellent substitutes for MSCs.Exosomes derived from MSCs(MSC-exosomes)have been demonstrated to be beneficial for cutaneous wound healing and accelerate the process through a variety of mechanisms.These mechanisms include alleviating inflammation,promoting vascularization,and promoting proliferation and migration of epithelial cells and fibroblasts.Therefore,the application of MSC-exosomes may be a promising alternative to cell therapy in the treatment of cutaneous wounds and could promote wound healing through multiple mechanisms simultaneously.This review will provide an overview of the role and the mechanisms of MSC-derived exosomes in cutaneous wound healing,and elaborate the potentials and future perspectives of MSC-exosomes application in clinical practice.
基金the Thailand Excellence Center for Tissue Engineering and Stem Cells,Faculty of Medicine,Chiang Mai University,for providing supporting research funds and facilities
文摘Objective:To investigate the biological effects of the Mucuna pruriens(M.pruriens)seed extracts that lacked of L-DOPA,which was formerly reported as the active ingredient,on erectile dysfunction(ED)both in vitro and in vivo.Methods:Seed of M.pruriens plant that cultivated in Mae Taeng District,Chiang Mai Province,Thailand,was collected.Component of its seeds were extracted and isolated into 2 fractions using methanol,polar and nonpolar.Each fraction was investigated for phytochemicals using GC/MS and was screened for biological activity In vitro using three different cell lines.The most biological active fraction was used to treat to both steptozotocin(STZ)-induced diabetes mellitus-erectile dysfunction(DM-ED)male wistar rats and normal rats(n=6 per groups)to compare the effect on sexual behaviour parameters,including number of intromission,mounting and ejaculation,with that of rats given Sildenafil by individually pairing with their female counterparts.Penile tissues and serums were collected to determine histological structure,related gene expression and biomolecules.Results:The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols,whereas the nonpolar fraction consisted of lipid derivatives.L-DOPA was not detected in either of the extracts.The polar fraction was able to up-regulate the expression of ED-related genes including e NOS and n NOS in vitro which subsequently promotes NO production and maintains intracellular cG MP levels.When administrated to DM-ED rats,the polar extract significantly improved all sexual behaviour parameters in DM-ED rats compare to untreated group(18.3±1.8 to 10.8±2.9 for intromission,9.8±2.2 to 5.7±1.3 for mounting,and 1.8±0.6 to 0.2±0.4 for ejaculation).That effect might due to the ability of the extract to stimulate the expression of eN OS and nN OS which results in NO production and subsequently maintains cG MP levels in penile tissue.Moreover,this extract may also prevent penile tissue deterioration due to diabetes.Conclusions:The polar extract of M.pruriens seed can be used for ED therapy,especially in patients with metabolic diseases including diabetes.The action of the extract might be due to catechol and its derivatives and polyphenols.
基金This work was supported by grants from the National Institute of Dental and Craniofacial Research,National Institutes of Health,Department of Health and Human Services(K99E025915 to C.C.)a Schoenleber Pilot Research Grant(to S.S.)from the University of Pennsylvania School of Dental Medicine,the Guangdong Financial Fund for High-Caliber Hospital Construction,the Postdoctoral Innovative Talents Support Program of China(BX20190380 to B.S.)the General Program of the China Postdoctoral Science Foundation(2019M663986 to B.S.).
文摘Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines remains elusive.Here,we reveal that even under physiological conditions,MSCs produce and release a low level of tumor necrosis factor alpha(TNFα),which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling.Furthermore,TNFαcritically maintains MSC function in vivo during bone homeostasis.Mechanistically,we unexpectedly discovered that physiological levels of TNFαsafeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFαbinds to mammalian target of rapamycin(mTOR)complex 2 and restricts mTOR signaling.Importantly,inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFαdeficiency and mechanical unloading.Collectively,these findings unravel the physiological framework of the dynamic TNFαshuttlebased mTOR equilibrium that governs MSC and bone homeostasis.
基金supported by the Program of the Scientific and Technological in Guiyang City(Grant No.Zhu Ke He[2020]-16-5)Program of Scientific and Technological Project in Guizhou Province(Grant No.[2020]4Y197,Qian Ke He Ji Chu ZK[2022]Yi Ban 516,Qian Ke He Ji Chu ZK[2021]Yi Ban 559)+3 种基金the Science and Technology Talents Growth Project in Education Department of Guizhou Province(Grant No.Qian Jiao He KY Zi[2021]4Y211)the Program of Science and Technology of Guizhou Provincial Health Commission(Grant No.gzwjkj2020-1-215)the Knowledge Innovation Special Project for Fundamental Research of Wuhan(Grant No.2022020801010461)the Sichuan Science and Technology Program(Grant No.2022NSFSC1420).
文摘Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens.Omiganan,an antimicrobial peptide,has shown promise for neutralizing endotoxins and eliminating diverse pathogens.However,its clinical application is hindered by safety and stability concerns.Herein,we present a nanoscale drug delivery system(Omi-hyd-Dex@HA NPs)that selectively targets infectious microenvironments(IMEs)and responds to specific stimuli for efficient intervention in sepsis.The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid(HA).The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes,but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase.The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation.In multiple tissue infection and sepsis animal models,Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction,thereby preventing subsequent fatal complications and significantly improving survival outcomes.The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.
基金supported by the National Natural Science Foundation of China(Nos.21976116 and 52161145409)the Shaanxi Science and Technology Program(No.2020KWZ-005)+1 种基金SAFEA of China(“Belt and Road”Innovative Exchange Foreign Expert Project,No.DL2021041001L)Researchers Supporting Project number(No.RSP-2021/149),King Saud University,Riyadh,Saudi Arabia。
文摘In the context of the circular economy,the huge amounts of biomass waste should be converted into value-added materials and energy to diminish pollution,atmospheric CO_(2)levels and costly waste disposal.Biological imaging usually uses expensive and toxic chemicals e.g.,organic dyes,semiconductor quantum dots,calling for safer,greener,cheaper fluorescent probes for biological imaging in vitro and in vivo.In these regards,carbon quantum dots(CQDs)-based fluorescent probes using biomass waste as a precursor may have much higher potential.Here we transformed the biomass waste of peach leaves into value-added fluorescent CQDs through a low-cost and green one-step hydrothermal process.The obtained CQDs show excitation-dependent photoluminescence properties with a fluorescence lifetime of 5.96 ns and a quantum yield of 7.71%without any passivation.In addition,the CQDs have a fine size of 1.9 nm with good hydrophilicity and high fluorescent stability over pH 4.0-11.0 range.Fluorescence imaging of in vitro cell cultures and in vivo with zebrafish show that CQDs possess ultra-low toxicity and remarkable performance for biological imaging.Even when CQDs present at a concentration as high as500μg/m L,the organism can still maintain more than 90%activity both in vitro and in vivo,and present bright fluorescence.The cheaper,greener,ultra-low toxicity CQDs developed in this work is a potential candidate for biological imaging in vitro and in vivo.
文摘BACKGROUND Streptococcus mitis(S.mitis)is an opportunistic pathogen that can lead to severe ocular infections.In previous reports,penetrating keratoplasty(PK)was usually adopted for the treatment of persistent corneal ulcers.This report describes an unusual case of nonhealing descemetocele caused by S.mitis treated by antibiotics plus amniotic membrane transplantation(AMT).CASE SUMMARY A 63-year-old woman presented with a right persistent corneal ulcer that she had suffered from for the past 9 mo.The culture of a corneal scraping yielded S.mitis.The right eye descemetocele decreased in diameter from 3 to 0.8 mm after the continuous administration of topical vancomycin and ceftriaxone for 2 wk.Due to the slow healing,AMT was performed.Her corneal erosion healed and gradually became clear.Her visual acuity recovered from initially counting fingers to 100/200 at the last follow-up,67 mo after AMT.CONCLUSION Antibiotics plus AMT may be an effective alternative treatment other than PK to promote epithelializationand to reduce inflammation in the corneas complicated by S. mitis keratitis.
基金Supported by Chang Gung Memorial Hospital,Linkou,Taiwan,No.CORPG3K0021 and No.CORPG3K0191.
文摘Dental stem cells can differentiate into different types of cells.Dental pulp stem cells,stem cells from human exfoliated deciduous teeth,periodontal ligament stem cells,stem cells from apical papilla,and dental follicle progenitor cells are five different types of dental stem cells that have been identified during different stages of tooth development.The availability of dental stem cells from discarded or removed teeth makes them promising candidates for tissue engineering.In recent years,three-dimensional(3D)tissue scaffolds have been used to reconstruct and restore different anatomical defects.With rapid advances in 3D tissue engineering,dental stem cells have been used in the regeneration of 3D engineered tissue.This review presents an overview of different types of dental stem cells used in 3D tissue regeneration,which are currently the most common type of stem cells used to treat human tissue conditions.
基金Supported by the National Program on Key Basic Research Project(973 Program)(2012CB720600,2012CB720603,2012CB720605)the National Natural Science Foundation of China(21432008,91413109,81373256,91213302)
文摘Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the excellent selectivity of AS1411 aptamer to targeted nucleolin-overexpressed cells, we used a fluorescent probe with a pH-sensitive function to label the AS1411 aptamer modified with azide by click-reaction. The spectral characteristics of fluorophore naphthalimide has a good pH dependence. By this way, nucleolin-overexpressed cell could be discriminated from normal cell. Further, this strategy could also discriminate the breast cancer tissue from the adjacent benign tissue in formalin-fixed and parrffin-embedded（FFPE） tissue specimens. It is considered that our method has the potential to be applied in medical detection.
基金supported by National Key R&D Program of China(Grant No.2024YFA1107800)National Natural Science Foundation of China(Grant Nos.82302395,82160355,and 82172105)+3 种基金Shanghai Sailing Program(Grant Nos.22YF1423200 and 22YF1437400)Shanghai Rising-Star Program(Grant No.24QB2704800)Taishan Scholar Program of Shandong Province(Grant No.tsqn202312359)Young Elite Scientists Sponsorship Program by CAST(Grant No.2023QNRC001).
文摘Tissue engineering strategies hold promise for constructing biomimetic tracheal substitutes to repair circum-ferential tracheal defects.However,current strategies for constructing off-the-shelf cartilage analogs for artificial trachea grafts face challenges of chondrocyte scarcity and inadequate culture strategies,which require extensive cell expansion and prolonged in vitro culture to generate robust neo-cartilage.To address these issues,we developed a nanofiber-hydrogel composite with superior mechanical performance by incorporating fragment oxidized bacterial cellulose(BC)nanofibers into a gelatin methacryloyl(GelMA)hydrogel network.Additionally,a biomaterial system was developed based on this composite,featuring dual-release functionality of fibroblast growth factor(FGF)and transforming growth factor beta(TGF-β)to facilitate step-wise maturation of neo-cartilage tissue.This process includes early-stage proliferation followed by second-stage extracellular matrix(ECM)deposition,driving the transition from proliferation to chondrogenesis.By encapsulating chondrocytes within the biomaterial system,mature neo-cartilage tissues with typical cartilage lacunae structures and abun-dant homogeneous cartilage-specific ECM deposition were successfully regenerated in vitro and in vivo.Furthermore,with a tailor-made growth factor-releasing strategy,the biomaterial system with low cell seeding density achieved biochemically and biomechanically functional neo-cartilage tissue regeneration,comparable to that achieved with high cell seeding density in the nanofiber-hydrogel composite.Based on the current biomaterial system,mature and functional cartilage-ring analogs were successfully constructed and applied to repair tracheal defects.Overall,the biomaterial system developed in this study provides a promising strategy for engineering transplantable,high-quality cartilage substitutes,with translational potential for artificial trachea construction.
基金supported by grants from the National Key Research and Development Program of China(2022YFA1104400)the National Natural Science Foundation of China(82170988,82371020,82301028,82401201,82471011)+5 种基金the Young Science and Technology Rising Star Project of Shaanxi Province(2024ZC-KJXX-122)the China Postdoctoral Science Foundation(BX20230485)the Project of State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration(2024MS04)the Shaanxi Provincial Health Research and Innovation Platform Construction Plan(2024PT-04)the“Rapid Response”Research projects(2023KXKT017 and 2023KXKT090)the Intramural Research Program project founded by Fourth Military Medical University(2024QMJJ008).
文摘Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In regenerative medicine,harnessing developmental principles for tissue repair offers promising therapeutic potential.Of particular interest is the condensation of progenitor cells,an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration.However,the precise cellular coordination mechanisms during condensation and regeneration remain elusive.Here,taking the tooth as a model organ,we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla,revealing a distinct Platelet-derived growth factor receptor alpha(PDGFRA)mesenchymal stem/stromal cell(MSC)population with remarkable odontogenic potential.Interestingly,a reciprocal paracrine interaction between PDGFRA^(+)dental follicle stem cells(DFSCs)and CD31^(+)Endomucin^(+)endothelial cells(ECs)was mediated by Vascular endothelial growth factor A(VEGFA)and Platelet-derived growth factor subunit BB(PDGFBB).This crosstalk not only maintains the functionality of PDGFRA^(+)DFSCs but also drives specialized angiogenesis.In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair.Collectively,our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis.These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
基金supported by the National Key Research and Development Program of China (2016YFC1101400 to Y.J.)the National Natural Science Foundation of China (31800817 to S.L., 31870970 to J.Z.)
文摘In modern medicine,bone and dental loss and defects are common and widespread morbidities,for which regenerative therapy has shown great promise.Mesenchymal stem cells,obtained from various sources and playing an essential role in organ development and postnatal repair,have exhibited enormous potential for regenerating bone and dental tissue.Currently,mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering.Nevertheless,the efficacy of MSCbased regeneration is not always fulfilled,especially in diseased microenvironments.Specifically,the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs,both as donors and recipients.Accordingly,approaches targeting a diseased microenvironment have been established,including improving the diseased niche to restore endogenous MSCs,enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies.Moreover,the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy.In this review,we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment,emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.
基金a grant from National High Technology Research and Development Program of China (863 Program) (2012AA020507)
文摘The development of cell biology, molecular biology, and material science, has been propelling biomimic tissue-engineered skins to become more sophisticated in scientificity and more simplified in practicality. In order to improve the safety, durability, elasticity, biocompatibility, and clinical efficacy of tissue-engineered skin, several powerful seed cells have already found their application in wound repair, and a variety of bioactive scaffolds have been discovered to influence cell fate in epidermogenesis. These exuberant interests provide insights into advanced construction strategies for complex skin mimics. Based on these exciting developments, a complete full-thickness tissue-engineered skin is likely to be generated.
基金financially supported by grants from the Nature Science Foundation of China (81620108007)National Key Research and Development Program of China (2016YFC1101400)+1 种基金Nature Science Foundation of China (31571532, 31601099)National Institutes of Health, Department of Health and Human Services (R01DE017449 to S.S.)
文摘Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A(p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells(MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/-mice by improving the function of endogenous MSCs.These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.
基金funded by grants from the National Natural Science Foundation of China (Nos. 81620108007 and 81870768)the National Key Research and Development Program of China (Nos. 2016YFC1101400 and 2017YFA0104800)the Scientific Young Alma of Shaanxi province (2018KJXX-015)。
文摘The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain,chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells(BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl+/- mice and BMSC-specific(Prrx1-alpl-/-) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca2+ influx, which it achieves by regulating L-type Ca2+ channel trafficking via binding to the α2δsubunits to regulate the internalization of the L-type Ca2+ channel. Decreased Ca2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca2+ flux through L-type Ca2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.
