Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell ba...Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.展开更多
The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion r...The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.展开更多
Bone marrow-derived mesenchymal stem cells （BMSCs） have been shown to promote the regeneration of injured peripheral nerves. Pulsed electromagnetic field （PEMF） reportedly promotes the proliferation and neuronal d...Bone marrow-derived mesenchymal stem cells （BMSCs） have been shown to promote the regeneration of injured peripheral nerves. Pulsed electromagnetic field （PEMF） reportedly promotes the proliferation and neuronal differentiation of BMSCs. Low-frequency PEMF can induce the neuronal differentiation of BMSCs in the absence of nerve growth factors. This study was designed to investigate the effects of low-frequency PEMF pretreatment on the proliferation and function of BMSCs and the effects of low-frequency PEMF pre-treated BMSCs on the regeneration of injured peripheral nerve using in vitro and in vivo experiments.In in vitro experiments, quantitative DNA analysis was performed to determine the proliferation of BMSCs, and reverse transcription-polymerase chain reaction was performed to detect S100 （Schwann cell marker）, glial fibrillary acidic protein （astrocyte marker）, and brain-derived neurotrophic factor and nerve growth factor （neurotrophic factors） mRNA expression. In the in vivo experiments, rat models of crush-injured mental nerve established using clamp method were randomly injected with low-frequency PEMF pretreated BMSCs, unpretreated BMSCs or PBS at the injury site （1 × 106 cells）. DiI-labeled BMSCs injected at the injury site were counted under the fluorescence microscope to determine cell survival. One or two weeks after cell injection, functional recovery of the injured nerve was assessed using the sensory test with von Frey filaments. Two weeks after cell injection, axonal regeneration was evaluated using histomorphometric analysis and retrograde labeling of trigeminal ganglion neurons. In vitro experiment results revealed that low-frequency PEMF pretreated BMSCs proliferated faster and had greater mRNA expression of growth factors than unpretreated BMSCs. In vivo experiment results revealed that compared with injection of unpretreated BMSCs, injection of low-frequency PEMF pretreated BMSCs led to higher myelinated axon count and axon density and more DiI-labeled neurons in the trigeminal ganglia, contributing to rapider functional recovery of injured mental nerve. These findings suggest that low-frequency PEMF pretreatment is a promising approach to enhance the efficacy of cell therapy for peripheral nerve injury repair.展开更多
Several studies have shown that fibroblast growth factor-2 （FGF2） can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the...Several studies have shown that fibroblast growth factor-2 （FGF2） can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2 （rhFGF2） treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/mL rhFGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/mL rhFGF2. Interestingly, treatment with 10 μg/mL rhFGF had a more obviously positive effect on the gap score than treatment with 50 μg/mL rhFGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rhFGF2 groups （10 μg/mL and 50 μg/mL） than in the PBS group. The 10 μg/mL rhFGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/mL rhFGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.展开更多
Galectins are a family of endogenousβglycan-binding proteins that play an important role in the modulation of inflammationassociated with neurodegeneration as seen in various neurological disorders such as dementia,m...Galectins are a family of endogenousβglycan-binding proteins that play an important role in the modulation of inflammationassociated with neurodegeneration as seen in various neurological disorders such as dementia,multiple sclerosis（MS）,Alzheimer’s disease（AD）（Chen et al.,2014）.展开更多
The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synt...The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or therapy.However,the function of cGAS in gastric cancer remains elusive.In this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines.By employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft mice.Mechanistically,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents.Furthermore,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.展开更多
Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have ...Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have shown that SARS-CoV-2 infection during pregnancy may increase the incidence of adverse outcomes.展开更多
Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables dir...Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.展开更多
During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella caus...During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential.However,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited.Here,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are infertile.The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes.We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm.Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in sperm.We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility.Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.展开更多
Vertebrate life begins with fertilization,and then the zygote genome is activated after transient silencing,a process termed zygotic genome activation(ZGA).Despite its fundamental role in totipotency and the initiatio...Vertebrate life begins with fertilization,and then the zygote genome is activated after transient silencing,a process termed zygotic genome activation(ZGA).Despite its fundamental role in totipotency and the initiation of life,the precise mechanism underlying ZGA initiation remains unclear.The existence of minor ZGA implies the possible critical role of noncoding RNAs in the initiation of ZGA.Here,we delineate the expression profile of long noncoding RNAs(lncRNAs)in early mouse embryonic development and elucidate their critical role in minor ZGA.Compared with protein-coding genes(PCGs),lncRNAs exhibit a stronger correlation with minor ZGA.Distinct H3K9me3 profiles can be observed between lncRNA genes and PCGs,and the enrichment of H3K9me3 before ZGA might explain the suspended expression of major ZGA-related PCGs despite possessing PolII pre-configuration.Furthermore,we identified the presence of PolII-enriched MuERV-L around the transcriptional start site of minor ZGA-related lncRNAs,and these repeats are responsible for the activation of minor ZGA-related lncRNAs and subsequent embryo development.Our study suggests that MuERV-L mediates minor ZGA lncRNA activation as a critical driver between epigenetic reprogramming triggered by fertilization and the embryo developmental program,thus providing clues for understanding the regulatory mechanism of totipotency and establishing bona fide totipotent stem cells.展开更多
Glioma is a common and malignant brain tumor,and molecular diagnostics for glioma have received increasing attention.1,2 Previous studies have suggested that the MAL2 gene may be involved in the transcytosis of variou...Glioma is a common and malignant brain tumor,and molecular diagnostics for glioma have received increasing attention.1,2 Previous studies have suggested that the MAL2 gene may be involved in the transcytosis of various cancers.3 This study aimed to investigate the potential of MAL2 as a biomarker for glioma.The candidate MAL2 CpG sites were validated by pyrosequencing and used to construct a diagnostic model for glioma.Survival analysis was also conducted to determine the relationship between highly methylated MAL2-specific CpG sites and the prognosis of glioma.The findings also showed that MAL2 was more highly methylated in glioma than in other cancers.The constructed diagnostic model can distinguish glioma from other cancers with high sensitivity(93.3%)and specificity(86.5%).Additionally,a risk score model was built based on MAL2 methylation to assess the prognosis of glioma。展开更多
The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection o...The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood.Here,we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy.Compared to control placentas,SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection.However,subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface.Notably,the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester.Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.展开更多
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease accompanied by persistent multiarticular synovitis and cartilage degradation. The present clinical treatments are limited to disease-modifying ant...Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease accompanied by persistent multiarticular synovitis and cartilage degradation. The present clinical treatments are limited to disease-modifying anti-rheumatic drugs (DMARDs) and aims to relieve pain and control the inflammation of RA. Despite considerable advances in the research of RA, the employment of current clinical procedure is enormous, hindered by systemic side effect, frequent administration, tolerance from long-lasting administration, and high costs. Emerging immunoengineering-based strategies, such as multiple immune-active nanotechnologies via mechanism-based immunology approaches, have been developed to improve specific targeting and to reduce adverse reactions for RA treatments. Here, we review recent studies in immunoengineering for the treatment of RA. The prospect of future immunoengineering treatment for RA has also been discussed.展开更多
The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to i...The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles,as well as compensatory effects among TET family members,which has made the understanding of the enzymatic role of TET not accurate enough.To solve this problem,we successfully generated mice catalytically inactive for specific Tet members(Tetm/m).We observed that,compared with the reported KO mice,mutant mice exhibited distinct developmental defects,including growth retardation,sex imbalance,infertility,and perinatal lethality.Notably,Tetm/mmouse embryonic stem cells(mESCs)were successfully established but entered an impaired developmental program,demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation.Intriguingly,Tet3,traditionally considered less critical for m ESCs due to its lower expression level,had a significant impact on the global hydroxymethylation,gene expression,and differentiation potential of mESCs.Notably,there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation.In summary,our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.展开更多
The dynamic changes in lipids during early embryonic development in mammals have not yet been comprehensively investigated.In a recent paper published in Nature Cell Biology,Zhang et al.reported the dynamic lipid land...The dynamic changes in lipids during early embryonic development in mammals have not yet been comprehensively investigated.In a recent paper published in Nature Cell Biology,Zhang et al.reported the dynamic lipid landscapes during preimplantation embryonic development in mice and humans.They highlight the crucial role of lipid unsaturation in regulating embryogenesis.展开更多
The development and maturation of follicles is a sophisticated and multistage process.The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this...The development and maturation of follicles is a sophisticated and multistage process.The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this process.In this study,we accurately classified the oocyte and follicle development into nine stages and profiled the gene expression of mouse oocytes and their surrounding granulosa cells and cumulus cells.The clustering of the transcriptomes showed the trajectories of two distinct development courses of oocytes and their surrounding somatic cells.Gene expression changes precipitously increased at Type 4 stage and drastically dropped afterward within both oocytes and granulosa cells.Moreover,the number of differentially expressed genes between oocytes and granulosa cells dramatically increased at Type 4 stage,most of which persistently passed on to the later stages.Strikingly,cell communications within and between oocytes and granulosa cells became active from Type 4 stage onward.Cell dialogs connected oocytes and granulosa cells in both unidirectional and bidirectional manners.TGFB2/3,TGFBR2/3,INHBA/B,and ACVR1/1B/2B of TGF-βsignaling pathway functioned in the follicle development.NOTCH signaling pathway regulated the development of granulosa cells.Additionally,many maternally DNA methylation-or H3K27me3-imprinted genes remained active in granulosa cells but silent in oocytes during oogenesis.Collectively,Type 4 stage is the key turning point when significant transcription changes diverge the fate of oocytes and granulosa cells,and the cell dialogs become active to assure follicle development.These findings shed new insights on the transcriptome dynamics and cell dialogs facilitating the development and maturation of oocytes and follicles.展开更多
Marrow niches in osteosarcoma(OS)are a specialized microenvironment that is essential for the maintenance and regulation of OS cells.However,existing animal xenograft models are plagued by variability,complexity,and h...Marrow niches in osteosarcoma(OS)are a specialized microenvironment that is essential for the maintenance and regulation of OS cells.However,existing animal xenograft models are plagued by variability,complexity,and high cost.Herein,we used a decellularized osteosarcoma extracellular matrix(dOsEM)loaded with extracellular vesicles from human bone marrow-derived stem cells(hBMSC-EVs)and OS cells as a bioink to construct a micro-osteosarcoma(micro-OS)through 3D printing.The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip(OOC)with a built-in recirculating perfusion system.The OOC system successfully integrated bone marrow niches,cell‒cell and cell-matrix crosstalk,and circulation,allowing a more accurate representation of OS characteristics in vivo.Moreover,the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS.展开更多
Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endom...Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just beginning.Using single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and EMJ.Within lesions,we identified unique epithelial(LGR5+)and invasive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between“invagination”and“metaplasia”theories of pathogenesis.Further,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways.Cell-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT cascades.This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.展开更多
Dear Editor,Human cell-based and personalized in vitro cartilage models are urgently needed for osteoarthritis treatment in pre-clinical regenerative medicine development.Cellular self-assemblies and condensations of ...Dear Editor,Human cell-based and personalized in vitro cartilage models are urgently needed for osteoarthritis treatment in pre-clinical regenerative medicine development.Cellular self-assemblies and condensations of the appropriate stem cells could initiate the formation of transient tissue structures programmed for specific organogenesis processes.1 This recapitulation of developmental events has previously been demonstrated for the formation of cardiac,epithelial and liver organoids.However,there has been very limited progress in the development of human cartilage organoids for osteoarthritis(OA).2 Here,we describe the fabrication of functional bioengineered cartilage organoid suitable for OA treatment.Briefly,agarose microwell inserts for formation of a high number of synovial mesenchymal stromal cell(SMSC)organoids with homogeneous size distribution were created as previously described by Leijten et al.33D-cultured SMSC organoids were generated and phenotypically analyzed for potential applications in OA modeling and treatment(Fig.1a).展开更多
基金Supported by New York State NYSTEM foundation,No.N08G-433
文摘Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.
基金This work was supported by the National Natural Science Foundation of China(Nos.81972058,81902194 and 82202680)the Science and Technology Commission of Shanghai Municipality(No.22YF1422900)+3 种基金the Shanghai Municipal Key Clinical Specialty,China(No.shslczdzk06701)the National Facility for Translational Medicine(Shanghai),China(No.TMSZ-2020-207)the Shanghai Engineering Research Center of Orthopedic Innovative Instruments and Personalized Medicine Instruments and Personalized Medicine(No.19DZ2250200)the Key R&D Program of Ningxia,China(Nos.2020BCH01001 and 2021BEG02037).
文摘The key to managing fracture is to achieve stable internal fixation,and currently,biologically and mechanically appropriate internal fixation devices are urgently needed.With excellent biocompatibility and corrosion resistance,titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures.However,the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined.Therefore,in this study,we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments.In vitro,we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity.Alkaline phosphatase(ALP)activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control.In the polymerase chain reaction experiment,the expression of osteogenic genes in the Ti45Nb group,such as ALP,osteopontin(OPN),osteocalcin(OCN),type 1 collagen(Col-1)and runt-related transcription factor-2(Runx2),was significantly higher than that in the control group.Meanwhile,in the western blot experiment,the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased,and the expression of PI3K–Akt-related proteins was also higher,which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway.In vivo,we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V,and the biosafety of Ti45Nb was confirmed by histological evaluation.Furthermore,immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway.Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway,and its good biosafety has been confirmed,which indicates its clinical translation potential.
基金supported by the National key Research and Development Program of China (2019YFC1709500)the National Collaboration Project of Critical Illness by Integrating Chinese Medicine and Western Medicine+8 种基金the Project of Heilongjiang Province Innovation Team “Tou Yan”the Yi-Xun Liu and Xiao-Ke Wu Academician Workstationthe Innovation Team of Reproductive Technique with Integrative Chinese Medicine and Western Medicine in Xuzhou City, ChinaHeilongjiang University of Chinese Medicine from the National Clinical Trial BaseHeilongjiang Provincial Clinical Research Center for Ovary Diseasesthe Research Grant Council (T13-602/21-N, C5045-20EF, and 14122021)Food and Health Bureau in Hong Kong, China (06171026)supported by a National Health and Medical Research Council (NHMRC) Investigator grant (GNT1176437)travel support from Merck.
基金supported by a grant of the Korea Health Technology R & D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(grant number:HI15C1535)
文摘Bone marrow-derived mesenchymal stem cells （BMSCs） have been shown to promote the regeneration of injured peripheral nerves. Pulsed electromagnetic field （PEMF） reportedly promotes the proliferation and neuronal differentiation of BMSCs. Low-frequency PEMF can induce the neuronal differentiation of BMSCs in the absence of nerve growth factors. This study was designed to investigate the effects of low-frequency PEMF pretreatment on the proliferation and function of BMSCs and the effects of low-frequency PEMF pre-treated BMSCs on the regeneration of injured peripheral nerve using in vitro and in vivo experiments.In in vitro experiments, quantitative DNA analysis was performed to determine the proliferation of BMSCs, and reverse transcription-polymerase chain reaction was performed to detect S100 （Schwann cell marker）, glial fibrillary acidic protein （astrocyte marker）, and brain-derived neurotrophic factor and nerve growth factor （neurotrophic factors） mRNA expression. In the in vivo experiments, rat models of crush-injured mental nerve established using clamp method were randomly injected with low-frequency PEMF pretreated BMSCs, unpretreated BMSCs or PBS at the injury site （1 × 106 cells）. DiI-labeled BMSCs injected at the injury site were counted under the fluorescence microscope to determine cell survival. One or two weeks after cell injection, functional recovery of the injured nerve was assessed using the sensory test with von Frey filaments. Two weeks after cell injection, axonal regeneration was evaluated using histomorphometric analysis and retrograde labeling of trigeminal ganglion neurons. In vitro experiment results revealed that low-frequency PEMF pretreated BMSCs proliferated faster and had greater mRNA expression of growth factors than unpretreated BMSCs. In vivo experiment results revealed that compared with injection of unpretreated BMSCs, injection of low-frequency PEMF pretreated BMSCs led to higher myelinated axon count and axon density and more DiI-labeled neurons in the trigeminal ganglia, contributing to rapider functional recovery of injured mental nerve. These findings suggest that low-frequency PEMF pretreatment is a promising approach to enhance the efficacy of cell therapy for peripheral nerve injury repair.
基金supported by a grant from the Korea Healthcare Technology R&D Project,Ministry for Health,Welfare&Family Affairs,Republic of Korea,No.A101578
文摘Several studies have shown that fibroblast growth factor-2 （FGF2） can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2 （rhFGF2） treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/mL rhFGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/mL rhFGF2. Interestingly, treatment with 10 μg/mL rhFGF had a more obviously positive effect on the gap score than treatment with 50 μg/mL rhFGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rhFGF2 groups （10 μg/mL and 50 μg/mL） than in the PBS group. The 10 μg/mL rhFGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/mL rhFGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.
文摘Galectins are a family of endogenousβglycan-binding proteins that play an important role in the modulation of inflammationassociated with neurodegeneration as seen in various neurological disorders such as dementia,multiple sclerosis（MS）,Alzheimer’s disease（AD）（Chen et al.,2014）.
基金supported by Zhengzhou Major Collaborative Innovation Project(No.18XTZX12003)Key Projects of Discipline Construction in Zhengzhou University(No.XKZDJC202001)+2 种基金National Key Research and Development Program in China(No.2020YFC2006100)Excellent Foreign Scientist Studio of Henan Province in China(No.GZS2018001)Medical Service Capacity Improvement Project of Henan Province in China(Grant No.Yu Wei Medicine[2017]No.66).
文摘The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or therapy.However,the function of cGAS in gastric cancer remains elusive.In this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines.By employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft mice.Mechanistically,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents.Furthermore,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.
基金supported by the Chinese National Program on the Key Basic Research Project(2021YFA1100300,2020YFA0112500)the National Natural Science Foundation of China(31721003,31820103009,32270856,32070857,32270858)。
文摘Dear Editor,Since the COVID-19 pandemic, the potential risks associated with maternal SARS-CoV-2 infection and its effect on fetal development have been a subject of considerable public concern. Previous studies have shown that SARS-CoV-2 infection during pregnancy may increase the incidence of adverse outcomes.
基金supported by the National Key Research and Development Program of China(2021YFC2701400)the National Natural Science Foundation of China(32000393,32322017,32288101)。
文摘Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.
基金supported by the National Key Research and Development Program of China(2021YFC2701400)in part by the National Natural Science Foundation of China(32000393 and 32288101).
文摘During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential.However,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited.Here,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are infertile.The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes.We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm.Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in sperm.We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility.Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.
基金supported by the National Key Research and Development Program of China(2018YFA0800101,2022YFC2702200,2019YFA0110000,2021YFA1100300,2022YFA1103103)the National Natural Science Foundation of China(32170801,31721003,31871489,32370870,31801243,31972882,32270858)the Fundamental Research Funds for the Central Universities(22120230292)。
文摘Vertebrate life begins with fertilization,and then the zygote genome is activated after transient silencing,a process termed zygotic genome activation(ZGA).Despite its fundamental role in totipotency and the initiation of life,the precise mechanism underlying ZGA initiation remains unclear.The existence of minor ZGA implies the possible critical role of noncoding RNAs in the initiation of ZGA.Here,we delineate the expression profile of long noncoding RNAs(lncRNAs)in early mouse embryonic development and elucidate their critical role in minor ZGA.Compared with protein-coding genes(PCGs),lncRNAs exhibit a stronger correlation with minor ZGA.Distinct H3K9me3 profiles can be observed between lncRNA genes and PCGs,and the enrichment of H3K9me3 before ZGA might explain the suspended expression of major ZGA-related PCGs despite possessing PolII pre-configuration.Furthermore,we identified the presence of PolII-enriched MuERV-L around the transcriptional start site of minor ZGA-related lncRNAs,and these repeats are responsible for the activation of minor ZGA-related lncRNAs and subsequent embryo development.Our study suggests that MuERV-L mediates minor ZGA lncRNA activation as a critical driver between epigenetic reprogramming triggered by fertilization and the embryo developmental program,thus providing clues for understanding the regulatory mechanism of totipotency and establishing bona fide totipotent stem cells.
基金the National Natural Science Foundation of China(No.82272116)Shanghai Municipal Science and Technology Major Project of China(No.2018SHZDZX01)+3 种基金ZJLab,Science and Technology Commission of Shanghai Municipality,China(No.20Z11900100,20S11905600)MOE Frontiers Center for Brain ScienceShanghai Shenkang,China(No.SHDC2020CR3073B)Shanghai Zhou Liangfu Medical Development Foundation“Brain Science and Brain Diseases Youth Innovation Program”.
文摘Glioma is a common and malignant brain tumor,and molecular diagnostics for glioma have received increasing attention.1,2 Previous studies have suggested that the MAL2 gene may be involved in the transcytosis of various cancers.3 This study aimed to investigate the potential of MAL2 as a biomarker for glioma.The candidate MAL2 CpG sites were validated by pyrosequencing and used to construct a diagnostic model for glioma.Survival analysis was also conducted to determine the relationship between highly methylated MAL2-specific CpG sites and the prognosis of glioma.The findings also showed that MAL2 was more highly methylated in glioma than in other cancers.The constructed diagnostic model can distinguish glioma from other cancers with high sensitivity(93.3%)and specificity(86.5%).Additionally,a risk score model was built based on MAL2 methylation to assess the prognosis of glioma。
基金supported by the Ministry of Science and Technology of China(2022YFC2702200,2021YFA1102900)the National Natural Science Foundation of China(Grant Nos.82022027,32270909,31721003,92168205,31871448,31820103009,and 32300684)+5 种基金supported by the key project of the Science and Technology of Shanghai Municipality(19JC1415300 and 21JC1405500)the Shanghai Municipal Medical and Health Discipline Construction Projects(2017ZZ02015)China Postdoctoral Science Foundation(2023M732660)the Postdoctoral Fellowship Program of CPSF(GZB20230523)Shanghai Municipal Health(Grant No.20214Y0254)Shanghai Pilot Program for Basic Research,Shanghai“Medical Academy Rising Star”Young Medical Talents Program,Shanghai First Maternity and Infant Hospital“Talent Reservoir”Sailing Program and the Fundamental Research Funds for the Central Universities.
文摘The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood.Here,we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy.Compared to control placentas,SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection.However,subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface.Notably,the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester.Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.
基金the National Science Foundation of China(82130073 and 61973206)Shanghai Leading Talents Program in 2020(110)+5 种基金Science and Technology Commission of Shanghai Municipality(23ZR1437600,23S31905900)Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiaotong University School of Medicine(2022LHA01)Science and Technology Commission of Shanghai Municipality(23S31905900)Shanghai Pujiang Program(21PJ1409200)China Postdoctoral Science Foundation(2022M722122)Shanghai Frontiers Science Center of Degen-eration and Regeneration in Skeletal System,and the Project of Biobank(YBKB202118)from Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine.
文摘Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease accompanied by persistent multiarticular synovitis and cartilage degradation. The present clinical treatments are limited to disease-modifying anti-rheumatic drugs (DMARDs) and aims to relieve pain and control the inflammation of RA. Despite considerable advances in the research of RA, the employment of current clinical procedure is enormous, hindered by systemic side effect, frequent administration, tolerance from long-lasting administration, and high costs. Emerging immunoengineering-based strategies, such as multiple immune-active nanotechnologies via mechanism-based immunology approaches, have been developed to improve specific targeting and to reduce adverse reactions for RA treatments. Here, we review recent studies in immunoengineering for the treatment of RA. The prospect of future immunoengineering treatment for RA has also been discussed.
基金supported by the National Key Research and Development Program of China(2020YFA0112500,2021YFA1100300,2021YFC2700300 and 2022YFC2702200)supported by the Fundamental Research Funds for the Central Universities+2 种基金National Natural Science Foundation of China(32070857 and 32270856,and 32270858)the Science and Technology Commission of Shanghai Municipality(23JC1403700)Peak Disciplines(TypeⅣ)of Institutions of Higher Learning in Shanghai。
文摘The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and development.Nevertheless,previous studies using knockdown(KD)or knockout(KO)models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles,as well as compensatory effects among TET family members,which has made the understanding of the enzymatic role of TET not accurate enough.To solve this problem,we successfully generated mice catalytically inactive for specific Tet members(Tetm/m).We observed that,compared with the reported KO mice,mutant mice exhibited distinct developmental defects,including growth retardation,sex imbalance,infertility,and perinatal lethality.Notably,Tetm/mmouse embryonic stem cells(mESCs)were successfully established but entered an impaired developmental program,demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation.Intriguingly,Tet3,traditionally considered less critical for m ESCs due to its lower expression level,had a significant impact on the global hydroxymethylation,gene expression,and differentiation potential of mESCs.Notably,there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation.In summary,our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.
文摘The dynamic changes in lipids during early embryonic development in mammals have not yet been comprehensively investigated.In a recent paper published in Nature Cell Biology,Zhang et al.reported the dynamic lipid landscapes during preimplantation embryonic development in mice and humans.They highlight the crucial role of lipid unsaturation in regulating embryogenesis.
基金supported by the National Key R&D Program of China(Grant Nos.2019YFA0110000 and 2021YFA1100300)the National Natural Science Foundation of China(Grant Nos.31972882,31721003,31771419,and 31900621)the Natural Science Foundation of Shanghai Municipality,China(Grant No.21ZR1465500)。
文摘The development and maturation of follicles is a sophisticated and multistage process.The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this process.In this study,we accurately classified the oocyte and follicle development into nine stages and profiled the gene expression of mouse oocytes and their surrounding granulosa cells and cumulus cells.The clustering of the transcriptomes showed the trajectories of two distinct development courses of oocytes and their surrounding somatic cells.Gene expression changes precipitously increased at Type 4 stage and drastically dropped afterward within both oocytes and granulosa cells.Moreover,the number of differentially expressed genes between oocytes and granulosa cells dramatically increased at Type 4 stage,most of which persistently passed on to the later stages.Strikingly,cell communications within and between oocytes and granulosa cells became active from Type 4 stage onward.Cell dialogs connected oocytes and granulosa cells in both unidirectional and bidirectional manners.TGFB2/3,TGFBR2/3,INHBA/B,and ACVR1/1B/2B of TGF-βsignaling pathway functioned in the follicle development.NOTCH signaling pathway regulated the development of granulosa cells.Additionally,many maternally DNA methylation-or H3K27me3-imprinted genes remained active in granulosa cells but silent in oocytes during oogenesis.Collectively,Type 4 stage is the key turning point when significant transcription changes diverge the fate of oocytes and granulosa cells,and the cell dialogs become active to assure follicle development.These findings shed new insights on the transcriptome dynamics and cell dialogs facilitating the development and maturation of oocytes and follicles.
基金the Shanghai Pujiang Program(21PJ1409200)the China Postdoctoral Science Foundation(2022M722122)+6 种基金Three-year Action Plan of Shenkang Development Center(SHDC2020CR2019B)Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiao Tong University School of Medicine(2022LHB07,2022LHA01)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal Systemthe Fundamental Research Funds for the Central Universities(YG2023LC07)Clinical Research Program of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine(JYLJ202122)the Project of Biobank from Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine(YBKB202116)the National Scientific Foundation of China(82171993,81972058,82130073).
文摘Marrow niches in osteosarcoma(OS)are a specialized microenvironment that is essential for the maintenance and regulation of OS cells.However,existing animal xenograft models are plagued by variability,complexity,and high cost.Herein,we used a decellularized osteosarcoma extracellular matrix(dOsEM)loaded with extracellular vesicles from human bone marrow-derived stem cells(hBMSC-EVs)and OS cells as a bioink to construct a micro-osteosarcoma(micro-OS)through 3D printing.The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip(OOC)with a built-in recirculating perfusion system.The OOC system successfully integrated bone marrow niches,cell‒cell and cell-matrix crosstalk,and circulation,allowing a more accurate representation of OS characteristics in vivo.Moreover,the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS.
基金National Natural Science Foundation of China(Nos.32270840,31721003 and 32270908)Shanghai Key Laboratory of Maternal Fetal Medicine(No.mfmkf202201)+1 种基金Natural Science Foundation of Zhejiang Province(No.LTGY24H040002)Jiaxing Municipal Public Welfare Research Project(No.2021AY30004).
文摘Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just beginning.Using single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and EMJ.Within lesions,we identified unique epithelial(LGR5+)and invasive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between“invagination”and“metaplasia”theories of pathogenesis.Further,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways.Cell-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT cascades.This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.
基金This work was funded by the National Key R&D Program of China(No.2018YFB1105600,No.2018YFA0703000)China National Natural Science Funds(No.51631009,No.81802122)+1 种基金Chinese post-doctoral funding(No.2019M661559)the Funds from Shanghai jiao tong university for the Clinical and Translational Research Center for 3D Printing Technology.
文摘Dear Editor,Human cell-based and personalized in vitro cartilage models are urgently needed for osteoarthritis treatment in pre-clinical regenerative medicine development.Cellular self-assemblies and condensations of the appropriate stem cells could initiate the formation of transient tissue structures programmed for specific organogenesis processes.1 This recapitulation of developmental events has previously been demonstrated for the formation of cardiac,epithelial and liver organoids.However,there has been very limited progress in the development of human cartilage organoids for osteoarthritis(OA).2 Here,we describe the fabrication of functional bioengineered cartilage organoid suitable for OA treatment.Briefly,agarose microwell inserts for formation of a high number of synovial mesenchymal stromal cell(SMSC)organoids with homogeneous size distribution were created as previously described by Leijten et al.33D-cultured SMSC organoids were generated and phenotypically analyzed for potential applications in OA modeling and treatment(Fig.1a).
