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
Dear Editor,Two distinct pathways,non-homologous end joining(NHEJ)and homologous recombination(HR)repair,have evolved to repair DNA double-strand breaks(DSBs),the most deleterious type of DNA damage.Impaired NHEJ and ...Dear Editor,Two distinct pathways,non-homologous end joining(NHEJ)and homologous recombination(HR)repair,have evolved to repair DNA double-strand breaks(DSBs),the most deleterious type of DNA damage.Impaired NHEJ and HR are often associated with a high incidence of tumorigenesis and the early onset of aging.A number of methods and tools have been developed to help elucidate the regulatory mechanisms of the two repair pathways in the past.In vitro biochemical assays employ 32P-labeled broken DNA fragments and cell extracts to evaluate DSB repair capacity.At DSB sites,several DSB repair factors form foci,which can be visualized through immunofluorescence and microscopy.Among them,phosphorylated H2AX at the Ser139 residue is often considered a DSB marker,and its formation and removal at different time points post the induction of DSBs can be used to reflect the repair capacity and genomic instability.In addition,by quantifying the kinetics of the recruitment of specific NHEJ and HR factors such as 53BP1,DNA-PKcs,MRE11,RPA2,and RAD51,one would be able to make judgments on whether NHEJ,HR,or both pathways is/are affected and sometimes at which steps DSB repair pathways are regulated.An alternative approach for kinetic analysis is to quantify the microirradiation-induced recruitment of repair factors.Moreover,comet assays are also utilized to measure DNA damage-induced genomic stability at the single-cell level.However,with these assays,it is still difficult to measure NHEJ and HR efficiency in a relatively less time-consuming and more quantitative manner.展开更多
Diabetic wound healing has become a serious healthcare challenge.The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular f...Diabetic wound healing has become a serious healthcare challenge.The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular function,and tissue necrosis.To solve these issues,we developed a double-network hydrogel,constructed with pluronic F127 diacrylate(F127DA)and hyaluronic acid methacrylate(HAMA),and enhanced by SS31-loaded mesoporous polydopamine nanoparticles(MPDA NPs).As components,SS31,a mitochondria-targeted peptide,maintains mitochondrial function,reduces mitochondrial reactive oxygen species(ROS)and thus regulates macrophage polarization,as well as promoting cell proliferation and migration,while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation,but also control release of SS31 in response to ROS.This F127DA/HAMA-MPDA@SS31(FH-M@S)hydrogel has characteristics of adhesion,superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31(M@S)NPs.In addition,in a diabetic rat full thickness skin defect model,the FH-M@S hydrogel promoted macrophage M2 polarization,collagen deposition,neovascularization and wound healing.Therefore,the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.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
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
Magnesium(Mg)alloys that have both antibacterial and osteogenic properties are suitable candidates for orthopedic implants.However,the fabrication of ideal Mg implants suitable for bone repair remains challenging beca...Magnesium(Mg)alloys that have both antibacterial and osteogenic properties are suitable candidates for orthopedic implants.However,the fabrication of ideal Mg implants suitable for bone repair remains challenging because it requires implants with interconnected pore structures and personalized geometric shapes.In this study,we fabricated a porous 3D-printed Mg-Nd-Zn-Zr(denoted as JDBM)implant with suitable mechanical properties using selective laser melting technology.The 3D-printed JDBM implant exhibited cytocompatibility in MC3T3-E1 and RAW267.4 cells and excellent osteoinductivity in vitro.Furthermore,the implant demonstrated excellent antibacterial ratios of 90.0% and 92.1% for methicillin-resistant S.aureus(MRSA)and Escherichia coli,respectively.The 3D-printed JDBM implant prevented MRSA-induced implant-related infection in a rabbit model and showed good in vivo biocompatibility based on the results of histological evaluation,blood tests,and Mg2+deposition detection.In addition,enhanced inflammatory response and TNF-α secretion were observed at the bone-implant interface of the 3D-printed JDBM implants during the early implantation stage.The high Mg^(2+)environment produced by the degradation of 3D-printed JDBM implants could promote M1 phenotype of macrophages(Tnf,iNOS,Ccl3,Ccl4,Ccl5,Cxcl10,and Cxcl2),and enhance the phagocytic ability of macrophages.The enhanced immunoregulatory effect generated by relatively fast Mg^(2+)release and implant degradation during the early implantation stage is a potential antibacterial mechanism of Mg-based implant.Our findings indicate that 3D-printed porous JDBM implants,having both antibacterial property and osteoinductivity,hold potential for future orthopedic applications.展开更多
Reconstruction of severe bone defects in revision total knee arthroplasty(TKA)remains a challenge for orthopaedists.The progression of medical imaging and additive manufacturing technology has enabled the rapid manufa...Reconstruction of severe bone defects in revision total knee arthroplasty(TKA)remains a challenge for orthopaedists.The progression of medical imaging and additive manufacturing technology has enabled the rapid manufacture of custom-made implants,and 3D-printed augments with interconnected pore structures have become an alternative approach for the reconstruction of bone defects in revision TKA,especially in patients with complex bone defects.The size and location of the bone defect were determined by thin-layer computed tomography(CT;layer thickness is 1 mm)after reduction of artifacts.The 3D reconstruction models of the host bone were obtained based on thin-layer CT imaging.The custom-made augmentation was designed according to the 3D reconstruction bone model.The augmentation had an interconnected porous structure on the bone-implant interface to achieve biological fixation.After the design was complete,the 3D model of augment was exported in STL format,and augments were fabricated with Ti6Al4V powder using electron beam melting.Thin-layer CT and 3D reconstruction bone models are accurate methods for evaluating periprosthetic bone loss after artifact reduction.The 3D-printed augments perfectly match the bone defects during surgery.3D-printed augmentation is an effective approach for the reconstruction of bone defects in revision TKA.Thus,surgeons and engineers should carefully evaluate the bone defect during augment design to avoid a mismatch between the augment and host bone.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the developme...Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.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
Embryonic stem cells(ESCs)and induced pluripotent stem cells(iPSCs)hold immense promise for regenerative medicine due to their abilities to self-renew and to differentiate into all cell types.This unique property is c...Embryonic stem cells(ESCs)and induced pluripotent stem cells(iPSCs)hold immense promise for regenerative medicine due to their abilities to self-renew and to differentiate into all cell types.This unique property is controlled by a complex interplay between transcriptional factors and epigenetic regulators.Recent research indicates that the epigenetic role of non-coding RNAs(ncRNAs)is an integral component of this regulatory network.This report will summarize fndings that focus on two classes of regulatory ncRNAs,microRNAs(miRNAs)and long ncRNAs(lncRNAs),in the induction,maintenance and directed differentiation of ESCs and iPSCs.Manipulating these two important types of ncRNAs would be crucial to unlock the therapeutic and research potential of pluripotent stem cells.展开更多
Regeneration of Intervertebral disc(IVD)is a scientific challenge because of the complex structure and composition of tissue,as well as the difficulty in achieving bionic function.Here,an anatomically correct IVD scaf...Regeneration of Intervertebral disc(IVD)is a scientific challenge because of the complex structure and composition of tissue,as well as the difficulty in achieving bionic function.Here,an anatomically correct IVD scaffold composed of biomaterials,cells,and growth factors were fabricated via three-dimensional(3D)bioprinting technology.Connective tissue growth factor(CTGF)and transforming growth factor-β3(TGF-β3)were loaded onto polydopamine nanoparticles,which were mixed with bone marrow mesenchymal stem cells(BMSCs)for regenerating and simulating the structure and function of the nucleus pulposus and annular fibrosus.In vitro experiments confirmed that CTGF and TGF-β3 could be released from the IVD scaffold in a spatially controlled manner,and induced the corresponding BMSCs to differentiate into nucleus pulposus like cells and annulus fibrosus like cells.Next,the fabricated IVD scaffold was implanted into the dorsum subcutaneous of nude mice.The reconstructed IVD exhibited a zone-specific matrix that displayed the corresponding histological and immunological phenotypes:primarily type II collagen and glycosaminoglycan in the core zone,and type I collagen in the surrounding zone.The testing results demonstrated that it exhibited good biomechanical function of the reconstructed IVD.The results presented herein reveal the clinical application potential of the dual growth factors-releasing IVD scaffold fabricated via 3D bioprinting.However,the evaluation in large mammal animal models needs to be further studied.展开更多
Over 50 years of efforts, cellular reprogramming opens a new door for disease modeling and regenerative medicine. Although induction of pluripotency by transcription factors has become common, only a small portion of ...Over 50 years of efforts, cellular reprogramming opens a new door for disease modeling and regenerative medicine. Although induction of pluripotency by transcription factors has become common, only a small portion of basic mechanisms of epigenetic modifications during this process have been revealed. To clearly understand reprogramming and devise ways to promote full transition towards pluripotency, we must gain insight from comprehensive characterizations of cells at distinct reprogramming stages, which involves gene expression profiling, chromatin state maps of key activating and repressive marks, and DNA modifications. Here, we review recent advances in epigenetic reprogramming to pluripotency with a focus on the principal molecular regulators and attach importance to the combination of high-throughput sequencing and systematic biology approaches in uncovering underlying molecular mechanisms of this unique platform in future researches.展开更多
Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essenti...Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.展开更多
2019 novel coronavirus disease has resulted in thousands of critically ill patients in China,which is a serious threat to people’s life and health.Severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)was report...2019 novel coronavirus disease has resulted in thousands of critically ill patients in China,which is a serious threat to people’s life and health.Severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)was reported to share the same receptor,angiotensin-converting enzyme 2(ACE2),with SARS-CoV.Here,based on the public single-cell RNA-sequencing database,we analyzed the mRNA expression profile of putative receptor ACE2 and AXL receptor tyrosine kinase(AXL)in the early maternal-fetal interface.The result indicates that the ACE2 has very low expression in the different cell types of early maternal-fetal interface,except slightly high in decidual perivascular cells cluster 1(PV1).Interestingly,we found that the Zika virus(ZIKV)receptor AXL expression is concentrated in perivascular cells and stromal cells,indicating that there are relatively more AXL-expressing cells in the early maternal-fetal interface.This study provides a possible infection route and mechanism for the SARS-CoV-2-or ZIKV-infected mother-to-fetus transmission disease,which could be informative for future therapeutic strategy development.展开更多
Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human dise...Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.展开更多
Embryonic stem cells possess fascinating capacity of self-renewal and developmental potential,leading to significant progress in understanding the molecular basis of pluripotency,disease modeling,and reprogramming tec...Embryonic stem cells possess fascinating capacity of self-renewal and developmental potential,leading to significant progress in understanding the molecular basis of pluripotency,disease modeling,and reprogramming technology.Recently,2-cell-like embryonic stem cells(ESCs)and expanded potential stem cells or extended pluripotent stem cells(EPSCs)generated from early-cleavage embryos display some features of totipotent embryos.These cell lines provide valuable in vitro models to study underlying principles of totipotency,cell plasticity,and lineage segregation.In this review,we summarize the current progress in this filed and highlight the application potentials of these cells in the future.展开更多
Poor oocyte quality is associated with early embryo developmental arrest and infertility.Maternal gene plays crucial roles in the regulation of oocyte maturation,and its mutation is a common cause of female infertilit...Poor oocyte quality is associated with early embryo developmental arrest and infertility.Maternal gene plays crucial roles in the regulation of oocyte maturation,and its mutation is a common cause of female infertility.However,how to improve oocyte quality and develop effective therapy for maternal gene mutation remains elusive.Here,we use Zar1 as an example to assess the feasibility of genome transfer to cure maternal gene mutationecaused female infertility.We first discover that cytoplasmic deficiency primarily leads to Zar1-null embryo developmental arrest by disturbing maternal transcript degradation and minor zygotic genome activation(ZGA)during the maternal-zygotic transition.We next perform genome transfer at the oocyte(spindle transfer or polar body transfer)and zygote(early pronuclear transfer or late pronuclear transfer)stages to validate the feasibility of preventing Zar1 mutationecaused infertility.We finally demonstrate that genome transfer either at the oocyte or at the early pronuclear stage can support normal preimplantation embryo development and produce live offspring.Moreover,those pups grow to adulthood and show normal fertility.Therefore,our findings provide an effective basis of therapies for the treatment of female infertility caused by maternal gene mutation.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the Chinese National Program on the Key Basic Research Project(2018YFC2000100 and 2021YFA1102000 to Z.M.)the National Natural Science Foundation of China(31871438 and 82071565 to Z.M.,81972457 and 32171288 to Y.J.)+2 种基金the“Shu Guang”project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation(19SG18 to Z.M.)the Program of the Shanghai Academic Research Leader(19XD1403000 to Z.M.)the Shanghai Sailing Program(22YF1434300 to Y.C.).
文摘Dear Editor,Two distinct pathways,non-homologous end joining(NHEJ)and homologous recombination(HR)repair,have evolved to repair DNA double-strand breaks(DSBs),the most deleterious type of DNA damage.Impaired NHEJ and HR are often associated with a high incidence of tumorigenesis and the early onset of aging.A number of methods and tools have been developed to help elucidate the regulatory mechanisms of the two repair pathways in the past.In vitro biochemical assays employ 32P-labeled broken DNA fragments and cell extracts to evaluate DSB repair capacity.At DSB sites,several DSB repair factors form foci,which can be visualized through immunofluorescence and microscopy.Among them,phosphorylated H2AX at the Ser139 residue is often considered a DSB marker,and its formation and removal at different time points post the induction of DSBs can be used to reflect the repair capacity and genomic instability.In addition,by quantifying the kinetics of the recruitment of specific NHEJ and HR factors such as 53BP1,DNA-PKcs,MRE11,RPA2,and RAD51,one would be able to make judgments on whether NHEJ,HR,or both pathways is/are affected and sometimes at which steps DSB repair pathways are regulated.An alternative approach for kinetic analysis is to quantify the microirradiation-induced recruitment of repair factors.Moreover,comet assays are also utilized to measure DNA damage-induced genomic stability at the single-cell level.However,with these assays,it is still difficult to measure NHEJ and HR efficiency in a relatively less time-consuming and more quantitative manner.
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.
文摘Diabetic wound healing has become a serious healthcare challenge.The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular function,and tissue necrosis.To solve these issues,we developed a double-network hydrogel,constructed with pluronic F127 diacrylate(F127DA)and hyaluronic acid methacrylate(HAMA),and enhanced by SS31-loaded mesoporous polydopamine nanoparticles(MPDA NPs).As components,SS31,a mitochondria-targeted peptide,maintains mitochondrial function,reduces mitochondrial reactive oxygen species(ROS)and thus regulates macrophage polarization,as well as promoting cell proliferation and migration,while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation,but also control release of SS31 in response to ROS.This F127DA/HAMA-MPDA@SS31(FH-M@S)hydrogel has characteristics of adhesion,superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31(M@S)NPs.In addition,in a diabetic rat full thickness skin defect model,the FH-M@S hydrogel promoted macrophage M2 polarization,collagen deposition,neovascularization and wound healing.Therefore,the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.
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).
基金supported by the National Natural Science Foundation of China(81972058,81902194,81902201,and 51821001)National Key R&D Program of China(2016YFC1100600,subproject 2016YFC1100604)+4 种基金Multicenter Clinical Research Project of Shanghai Jiao Tong University School of Medicine,China(DLY201506)High Technology and Key Development Project of Ningbo,China(2019B10102)Shanghai Municipal Key Clinical Specialty,China(shslczdzk06701)National Facility for Translational Medicine(Shanghai),China(TMSZ-2020-207)the Interdisciplinary Program of Shanghai Jiao Tong University,China(YG2019QN2019).
文摘Magnesium(Mg)alloys that have both antibacterial and osteogenic properties are suitable candidates for orthopedic implants.However,the fabrication of ideal Mg implants suitable for bone repair remains challenging because it requires implants with interconnected pore structures and personalized geometric shapes.In this study,we fabricated a porous 3D-printed Mg-Nd-Zn-Zr(denoted as JDBM)implant with suitable mechanical properties using selective laser melting technology.The 3D-printed JDBM implant exhibited cytocompatibility in MC3T3-E1 and RAW267.4 cells and excellent osteoinductivity in vitro.Furthermore,the implant demonstrated excellent antibacterial ratios of 90.0% and 92.1% for methicillin-resistant S.aureus(MRSA)and Escherichia coli,respectively.The 3D-printed JDBM implant prevented MRSA-induced implant-related infection in a rabbit model and showed good in vivo biocompatibility based on the results of histological evaluation,blood tests,and Mg2+deposition detection.In addition,enhanced inflammatory response and TNF-α secretion were observed at the bone-implant interface of the 3D-printed JDBM implants during the early implantation stage.The high Mg^(2+)environment produced by the degradation of 3D-printed JDBM implants could promote M1 phenotype of macrophages(Tnf,iNOS,Ccl3,Ccl4,Ccl5,Cxcl10,and Cxcl2),and enhance the phagocytic ability of macrophages.The enhanced immunoregulatory effect generated by relatively fast Mg^(2+)release and implant degradation during the early implantation stage is a potential antibacterial mechanism of Mg-based implant.Our findings indicate that 3D-printed porous JDBM implants,having both antibacterial property and osteoinductivity,hold potential for future orthopedic applications.
基金the 3D Snowball Project of Shanghai Jiao Tong University School of Medicine(No.GXQ202007)the Natural Science Foundation of Shanghai(No.20ZR1432000)+2 种基金the Project of Shanghai Collaborative Innovation Center for Translational Medicine(No.TM201814)the Clinical Research Program of the 9th People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(No.JYLJ025)the National Natural Science Foundation of China(No.81772425)。
文摘Reconstruction of severe bone defects in revision total knee arthroplasty(TKA)remains a challenge for orthopaedists.The progression of medical imaging and additive manufacturing technology has enabled the rapid manufacture of custom-made implants,and 3D-printed augments with interconnected pore structures have become an alternative approach for the reconstruction of bone defects in revision TKA,especially in patients with complex bone defects.The size and location of the bone defect were determined by thin-layer computed tomography(CT;layer thickness is 1 mm)after reduction of artifacts.The 3D reconstruction models of the host bone were obtained based on thin-layer CT imaging.The custom-made augmentation was designed according to the 3D reconstruction bone model.The augmentation had an interconnected porous structure on the bone-implant interface to achieve biological fixation.After the design was complete,the 3D model of augment was exported in STL format,and augments were fabricated with Ti6Al4V powder using electron beam melting.Thin-layer CT and 3D reconstruction bone models are accurate methods for evaluating periprosthetic bone loss after artifact reduction.The 3D-printed augments perfectly match the bone defects during surgery.3D-printed augmentation is an effective approach for the reconstruction of bone defects in revision TKA.Thus,surgeons and engineers should carefully evaluate the bone defect during augment design to avoid a mismatch between the augment and host bone.
基金the Ethics Committee of Zhongnan Hospital ofWuhan University(permit number:KELUN2017082 and KELUN2020100)The tissue samples were obtained with written informed consent from each patient.All animal experiments were approved in accordance with the guidelines of the Animal Ethics and Welfare Committee of Wuhan University of Zhongnan Hospital(permit number:ZN2022005).
文摘Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
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 grants from the Ministry of Science and Technology of China(Grant No.2011CB965100,2011DFA30480,2010CB944900,2010CB945000,2012CB966603,2011CBA01100 and 2013CB967401)the National Natural Science Foundation of China(Grant No.31210103905,91219305,31201107,31101061,81170499,31071306,31000378 and 31171432)+2 种基金the Science and Technology Commission of Shanghai Municipality(Grant No.12ZR1450900,11ZR1438500 and 11XD1405300)Ministry of Education of China(Grant No.IRT1168 and 20110072110039)supported by Fundamental Research Funds for the Central Universities(Grant No.2000219066,2000219067 and 2000219077)
文摘Embryonic stem cells(ESCs)and induced pluripotent stem cells(iPSCs)hold immense promise for regenerative medicine due to their abilities to self-renew and to differentiate into all cell types.This unique property is controlled by a complex interplay between transcriptional factors and epigenetic regulators.Recent research indicates that the epigenetic role of non-coding RNAs(ncRNAs)is an integral component of this regulatory network.This report will summarize fndings that focus on two classes of regulatory ncRNAs,microRNAs(miRNAs)and long ncRNAs(lncRNAs),in the induction,maintenance and directed differentiation of ESCs and iPSCs.Manipulating these two important types of ncRNAs would be crucial to unlock the therapeutic and research potential of pluripotent stem cells.
基金This study was supported by grants from the National Natural Science Foundation of China （31030050, 81520108004, and 81470422 to H.-T.Y.）, the Strategic Priority Research Program of Chinese Academy of Sciences （XDA01020204 to H.-T.Y.）, the National Basic Research Program of China （2014CB965100 to H.-T.Y.）, the National Science and Technology Major Project （2012ZX09501001 to H.-T.Y.）, and the Shenzhen Science, Technology and Innovation Committee OCYI 20160428154108239 to K.O.）.
基金supported by National Key R&D Program of China(No.2018YFB1105600,No.2018YFA0703000)National Natural Science Foundation of China(No.81802131)Project funded by China Postdoctoral Science Foundation(No.2019T120347)and the fund of No.XK2019013.
文摘Regeneration of Intervertebral disc(IVD)is a scientific challenge because of the complex structure and composition of tissue,as well as the difficulty in achieving bionic function.Here,an anatomically correct IVD scaffold composed of biomaterials,cells,and growth factors were fabricated via three-dimensional(3D)bioprinting technology.Connective tissue growth factor(CTGF)and transforming growth factor-β3(TGF-β3)were loaded onto polydopamine nanoparticles,which were mixed with bone marrow mesenchymal stem cells(BMSCs)for regenerating and simulating the structure and function of the nucleus pulposus and annular fibrosus.In vitro experiments confirmed that CTGF and TGF-β3 could be released from the IVD scaffold in a spatially controlled manner,and induced the corresponding BMSCs to differentiate into nucleus pulposus like cells and annulus fibrosus like cells.Next,the fabricated IVD scaffold was implanted into the dorsum subcutaneous of nude mice.The reconstructed IVD exhibited a zone-specific matrix that displayed the corresponding histological and immunological phenotypes:primarily type II collagen and glycosaminoglycan in the core zone,and type I collagen in the surrounding zone.The testing results demonstrated that it exhibited good biomechanical function of the reconstructed IVD.The results presented herein reveal the clinical application potential of the dual growth factors-releasing IVD scaffold fabricated via 3D bioprinting.However,the evaluation in large mammal animal models needs to be further studied.
基金supported by the National Natural Science Foundation of China(31325019,91319306 and31401247)Ministry of Science and Technology of China(2015CB964800 and 2014CB964601)
文摘Over 50 years of efforts, cellular reprogramming opens a new door for disease modeling and regenerative medicine. Although induction of pluripotency by transcription factors has become common, only a small portion of basic mechanisms of epigenetic modifications during this process have been revealed. To clearly understand reprogramming and devise ways to promote full transition towards pluripotency, we must gain insight from comprehensive characterizations of cells at distinct reprogramming stages, which involves gene expression profiling, chromatin state maps of key activating and repressive marks, and DNA modifications. Here, we review recent advances in epigenetic reprogramming to pluripotency with a focus on the principal molecular regulators and attach importance to the combination of high-throughput sequencing and systematic biology approaches in uncovering underlying molecular mechanisms of this unique platform in future researches.
基金the National Key R&D Program of China (2016YFA0100400)the National Natural Science Foundation of China (31721003)+6 种基金the Ministry of Science and Technology of China (2015CB964800, 2015CB964503, and 2018YFA0108900)the National Natural Science Foundation of China (81630035, 31871446, and 31771646)the Shanghai Rising-Star Program (17QA1404200)the Shanghai Chenguang Program (16CG17)the Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015)National Postdoctoral Program for Innovative Talents (BX201700307)China Postdoctoral Science Foundation (2017M621527).
文摘Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.
基金supported by the Key Program of the National Natural Science Foundation of China(81730039)the National Natural Science Foundation of China(81671460,81871167)+4 种基金the National Key Research and Development Program of China(2017YFC1001401)Shanghai Municipal Medical and Health Discipline Constniction Projects(2017ZZ02015)the National Basic Research Program of China(2015CB943300)the Program for Shanghai leaders to Li-Ping Jinthe Natural Science Foundation of Shanghai(18ZR1430000)to Qingliang Zheng.
文摘2019 novel coronavirus disease has resulted in thousands of critically ill patients in China,which is a serious threat to people’s life and health.Severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)was reported to share the same receptor,angiotensin-converting enzyme 2(ACE2),with SARS-CoV.Here,based on the public single-cell RNA-sequencing database,we analyzed the mRNA expression profile of putative receptor ACE2 and AXL receptor tyrosine kinase(AXL)in the early maternal-fetal interface.The result indicates that the ACE2 has very low expression in the different cell types of early maternal-fetal interface,except slightly high in decidual perivascular cells cluster 1(PV1).Interestingly,we found that the Zika virus(ZIKV)receptor AXL expression is concentrated in perivascular cells and stromal cells,indicating that there are relatively more AXL-expressing cells in the early maternal-fetal interface.This study provides a possible infection route and mechanism for the SARS-CoV-2-or ZIKV-infected mother-to-fetus transmission disease,which could be informative for future therapeutic strategy development.
基金supported by the National Natural Science Foundation of China(31871380,32000500,32070730,32170756,32170804,81330008,81671377,81725010,81725010,81872874,81921006,81922027,81971312,81991512,82030041,82103167,82122024,82125009,82125011,82130044,91749126,91949101,91949207,92049302)the National Key Research and Development Program of China(2017YFA0506400,2018YFA0800200,2018YFA0800700,2018YFA0900200,2018YFC2000100,2018YFC2000400,2018YFE-0203700,20192ACB70002,2019YFA0802202,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002800,2020YFC-2002900,2021ZD0202401)+11 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100,XDA16010603,XDA16020400,XDB29020000,XDB39000000,XDB39000000,XDB39030300)the China Association for Science and Technology(2021QNRC001)the Beijing Municipal Science and Technology Commission(Z200022)the Natural Science Foundation of Shanghai(21JC1406400)the Key Programs of the Jiangxi ProvinceChina(20192ACB70002)the“Shu Guang”Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation(19SG18)the Shanghai Sailing Program(22YF1434300)the Research Project of Joint Laboratory of University of Science and Technology of China and Anhui Mental Health Center(2019LH03)the Fundamental Research Funds for the Central Universities(WK2070210004)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology(YESS20210002)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022083)。
文摘Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.
基金supported by the National Natural Science Foundation of China(31970758)National Key R&D Program of China(2016YFA0102200,2017YFA0103301,2018YFC1004001)。
文摘Embryonic stem cells possess fascinating capacity of self-renewal and developmental potential,leading to significant progress in understanding the molecular basis of pluripotency,disease modeling,and reprogramming technology.Recently,2-cell-like embryonic stem cells(ESCs)and expanded potential stem cells or extended pluripotent stem cells(EPSCs)generated from early-cleavage embryos display some features of totipotent embryos.These cell lines provide valuable in vitro models to study underlying principles of totipotency,cell plasticity,and lineage segregation.In this review,we summarize the current progress in this filed and highlight the application potentials of these cells in the future.
基金primarily supported by the Ministry of Science and Technology of the People’s Republic of China(2017YFA0102602,2016YFA0100400)supported by the National Natural Science Foundation of China(81630035,31871448,31721003)+3 种基金the Shanghai Subject Chief Scientist Program(15XD1503500)Supporting Project of Medical Guidance(Western Medicine)of Science and Technology Commission of Shanghai Municipality(15411964600)Merck Serono China Research Fund for Fertility Experts,the Shanghai municipal medical and health discipline construction projects(2017ZZ02015)the Fundamental Research Funds for the Central Universities(1515219049)。
文摘Poor oocyte quality is associated with early embryo developmental arrest and infertility.Maternal gene plays crucial roles in the regulation of oocyte maturation,and its mutation is a common cause of female infertility.However,how to improve oocyte quality and develop effective therapy for maternal gene mutation remains elusive.Here,we use Zar1 as an example to assess the feasibility of genome transfer to cure maternal gene mutationecaused female infertility.We first discover that cytoplasmic deficiency primarily leads to Zar1-null embryo developmental arrest by disturbing maternal transcript degradation and minor zygotic genome activation(ZGA)during the maternal-zygotic transition.We next perform genome transfer at the oocyte(spindle transfer or polar body transfer)and zygote(early pronuclear transfer or late pronuclear transfer)stages to validate the feasibility of preventing Zar1 mutationecaused infertility.We finally demonstrate that genome transfer either at the oocyte or at the early pronuclear stage can support normal preimplantation embryo development and produce live offspring.Moreover,those pups grow to adulthood and show normal fertility.Therefore,our findings provide an effective basis of therapies for the treatment of female infertility caused by maternal gene mutation.
