Dear Editor, Human embryonic stem （ES） cells possess the potential to differentiate into all the cell types of the human body and provide potential applications in regenerative medicine . However, the concerns of i...Dear Editor, Human embryonic stem （ES） cells possess the potential to differentiate into all the cell types of the human body and provide potential applications in regenerative medicine . However, the concerns of immune rejection hamper transplantation therapies using human ES cells. To avoid the complications of immune rejection, diverse methods, such as somatic nuclear transfer （also called therapeutic cloning） and fusion of somatic ceils with human ES ceils , have been attempted to produce patient-specific pluripotent stem cells. Most of these approaches have resulted in little success. The generation of human iPS cells （induced展开更多
There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B （NF-κB）, a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Altho...There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B （NF-κB）, a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-κB activation in inflammatory bowel diseases （IBDs） increases risk of colorectal cancer （CRC） in the patients with the number of years of active disease. NF-κB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-κB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation （Cyclin D1）, angiogenesis （VEGF, IL-8, COX2）, and metastasis （MMP9）. These findings implicate NF-κB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-r,B subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-κB family, it will be a long time before the coming of targeting NF-κB in CRC therapy.展开更多
Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and have diverse functions during development and organogenesis. BMPs play a major role in skeletal development and bone formation, and disrupti...Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and have diverse functions during development and organogenesis. BMPs play a major role in skeletal development and bone formation, and disruptions in BMP signaling cause a variety of skeletal and extraskeletal anomalies. Several knockout models have provided insight into the mechanisms responsible for these phenotypes. Proper bone formation requires the differentiation of osteoblasts from mesenchymal stem cell (MSC) precursors, a process mediated in part by BMP signaling. Multiple BMPs, including BMP2, BMP6, BMP7 and BMP9, promote osteoblastic differentiation of MSCs both in vitro and in vivo. BMP9 is one of the most osteogenic BMPs, yet it is a poorly characterized member of the BMP family. Several studies demonstrate that the mechanisms controlling BMP9-mediated osteogenesis differ from other osteogenic BMPs, but little is known about these specific mechanisms. Several pathways critical to BMP9-mediated osteogenesis are also important in the differentiation of other cell lineages, including adipocytes and chondrocytes. BMP9 has also demonstrated translational promise in spinal fusion and bone fracture repair. This review will summarize our current knowledge of BMP-mediated osteogenesis, with a focus on BMP9, by presenting recently completed work which may help us to further elucidate these pathways.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
Dear Editor： The demonstration that four transcription factors, Oct4/Sox2/Myc/Klf4, can reprogram fibroblasts into ES-like cells or induced pluripotent stem cells （iPS cells） has generated tremendous interests not...Dear Editor： The demonstration that four transcription factors, Oct4/Sox2/Myc/Klf4, can reprogram fibroblasts into ES-like cells or induced pluripotent stem cells （iPS cells） has generated tremendous interests not only in the field of stem cell biology, but also those related fields such as developmental biology and regenerative medicine [1-5]. The advance has greatly improved the prospects of generating patient specific pluripotent stem cells for therapeutic purposes without therapeutic cloning, an approach with formidable technical as well as ethical challenges. The conceptual breakthrough of the iPS strategy is quite obvious, demonstrating for the first time that the reprogramming of somatic nuclei can be achieved through a rational combination of transcription factors with defined regulatory activities, in contrast to the ill defined reprogramming power of unfertilized eggs. However, the application of the iPS strategy is so far limited to mouse fibroblasts carrying engineered selection markers [3, 4]. The need for selection using drug resistance or marker driven by Nanog-or Oct4-promoters would hamper not only its application in human therapy, but also any at- tempts to popularize this exciting experimental approach to other species such as primates. We reason that cells reprogrammed by Oct4/Sox2/Myc/Klf4 can be identified morphologically among the parental fibroblasts and the acquired pluripotent property should offer a growth advantage over their parental fibroblasts.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
BACKGROUND Premature ovarian failure(POF)affects many adult women less than 40 years of age and leads to infertility.According to previous reports,various tissue-specific stem cells can restore ovarian function and fo...BACKGROUND Premature ovarian failure(POF)affects many adult women less than 40 years of age and leads to infertility.According to previous reports,various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF.Human embryonic stem cells(ES)provide an alternative source for mesenchymal stem cells(MSCs)because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics.Embryonic stem cell-derived mesenchymal stem cells(ES-MSCs)are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs.However,possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated.AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells(BMMSCs)in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure.METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF.Either human ES-MSCs or BMMSCs were transplanted into these mice.Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ESMSCs and/or BM-MSCs,we evaluated body weight,estrous cyclicity,folliclestimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation.Moreover,terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling,real-time PCR,Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation.Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor,insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function.RESULTS The human ES-MSCs significantly restored hormone s展开更多
Vascular injury,remodeling,as well as angiogenesis,are the leading causes of coronary or cerebrovascular disease.The blood vessel functional imbalance trends to induce atherosclerosis,hypertension,and pulmonary arteri...Vascular injury,remodeling,as well as angiogenesis,are the leading causes of coronary or cerebrovascular disease.The blood vessel functional imbalance trends to induce atherosclerosis,hypertension,and pulmonary arterial hypertension.As several genes have been identified to be dynamically regulated during vascular injury and remodeling,it is becoming widely accepted that several types of non-coding RNA,such as microRNAs(miRNAs)and long non-coding RNAs(lncRNAs),are involved in regulating the endothelial cell and vascular smooth muscle cell(VSMC)behaviors.Here,we review the progress of the extant studies on mechanistic,clinical and diagnostic implications of miRNAs and lncRNAs in vascular injury and remodeling,as well as angiogenesis,emphasizing the important roles of miRNAs and lncRNAs in vascular diseases.Furthermore,we introduce the interaction between miRNAs and lncRNAs,and highlight the mechanism through which lncRNAs are regulating the miRNA function.We envisage that continuous in-depth research of non-coding RNAs in vascular disease will have significant implications for the treatment of coronary or cerebrovascular diseases.展开更多
Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and s...Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and sirtuins(SIRTs).Among them,sirtuins are known as a protein family with versatile functions,such as metabolic control,epigenetic modification and lifespan extension.Therefore,by understanding how sirtuins regulate metabolic processes,we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation.Here,we review the biology of SIRT3,SIRT4,and SIRT5,known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix.First,we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation.Then,we will summarize the current knowledge about functional differences between SIRT3,SIRT4,and SIRT5 in metabolic control and integration in signaling networks.Finally,we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.展开更多
The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats(CRISPR) and programmable nucleases to make precise modifications to geneti...The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats(CRISPR) and programmable nucleases to make precise modifications to genetic material, has provided enormous opportunities to advance biomedical research and promote human health. The application of these technologies in basic biomedical research has yielded significant advances in identifying and studying key molecular targets relevant to human diseases and their treatment. The clinical translation of genome editing techniques offers unprecedented biomedical engineering capabilities in the diagnosis, prevention, and treatment of disease or disability. Here, we provide a general summary of emerging biomedical applications of genome editing, including open challenges. We also summarize the tools of genome editing and the insights derived from their applications, hoping to accelerate new discoveries and therapies in biomedicine.展开更多
Many human genetic diseases,including Hutchinson-Gilford progeria syndrome(HGPS),are caused by single point mutations.HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutati...Many human genetic diseases,including Hutchinson-Gilford progeria syndrome(HGPS),are caused by single point mutations.HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene.Base editors(BEs)composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions.Here,we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA(gRNA)targeting the LMNA gene via microinjection into monkey zygotes.Five out of six newborn monkeys carried the mutation specifically at the target site.HGPS monkeys expressed the toxic form of lamin A,progerin,and recapitulated the typical HGPS phenotypes including growth retardation,bone alterations,and vascular abnormalities.Thus,this monkey model genetically and clinically mimics HGPS in humans,demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.展开更多
GUoma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase （IDH） mutations in up to 80% lower grade gUomas （LGG） and in 76% secondary gUoblastomas （GBM）. ...GUoma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase （IDH） mutations in up to 80% lower grade gUomas （LGG） and in 76% secondary gUoblastomas （GBM）. IDH mutations are also seen in 10%-20% of acute myeloid leukemia （AML）. In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells （pre-LSCs） stage, whereas mutations in genes propa- gating oncogenic signal are late events in leukemia. IDH mutations are also early events in gUoma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in gUoma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD# as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK#, FIPIL1, or FUBP1 collaborate with IDH mutations to negatively affect patients＇ survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4, at gen- etic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and gUoma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premaUgnant stem cells to gUoma.展开更多
Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking....Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.展开更多
One important aspect of mesenchymal stromal cells （MSCs）-mediated immunomodulation is the recruitment and induction of regulatory T （Treg） cells. However, we do not yet know whether MSCs have similar effects on th...One important aspect of mesenchymal stromal cells （MSCs）-mediated immunomodulation is the recruitment and induction of regulatory T （Treg） cells. However, we do not yet know whether MSCs have similar effects on the other subsets of Treg cells. Herein, we studied the effects of MSCs on CD8＋CD28- Treg cells and found that the MSCs could not only increase the proportion of CD8＋CD28- T cells, but also enhance CD8＋CD28-T cells＇ ability of hampering naive CD4＋ T-cell proliferation and activation, decreasing the production of IFN-γ by activated CD4＋ T cells and inducing the apoptosis of activated CD4＋ T cells. Mechanistically, the MSCs affected the functions of the CD8＋CD28- T cells partially through moderate upregulating the expression of IL-10 and FasL. The MSCs had no distinct effect on the shift from CD8＋CD28＋ T cells to CD8＋CD28- T cells, but did increase the proportion of CD8＋CD28- T cells by reducing their rate of apoptosis. In summary, this study shows that MSCs can enhance the regulatory function of CD8＋CD28- Treg cells, shedding new light on MSCs-mediated immune regulation.展开更多
Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem ce...Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.展开更多
The percentage of elderly people in the world is increasing at an unprecedented pace;so it is in China, which has the world s largest population and a high ratio of the seniors (aged 60 and above) to working-age adult...The percentage of elderly people in the world is increasing at an unprecedented pace;so it is in China, which has the world s largest population and a high ratio of the seniors (aged 60 and above) to working-age adults. The growing elderly population is presenting a major social challenge. Accordingly, it is not only imperative as a national strategic demand but also promises great scientific values to understand the biological process of aging, explore the mystery of healthy aging, delay the aging process, and treat the age-related diseases. This Perspective summarizes past and present advances of the basic and translational aging research in China and offers perspectives on future endeavors in this area.展开更多
Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a p...Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.展开更多
The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.H...The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.展开更多
Dear Editor： Gao et al. published data in Nature Biotechnology （Nat Biotechnol. 2016 May 2） showing that DNA-guided genome editing using the Natronobacterium gregoryi Argonaute （NgAgo） protein targeted 47 mammali...Dear Editor： Gao et al. published data in Nature Biotechnology （Nat Biotechnol. 2016 May 2） showing that DNA-guided genome editing using the Natronobacterium gregoryi Argonaute （NgAgo） protein targeted 47 mammalian genomic loci with a 100% success rate and an efficiency of 21.3%-41.3% at various targets. This report led us to test NgAgo＇s utility in various cells and organisms such as mouse and zebrafish for gene editing.展开更多
Diabetes-associated periodontitis(DP)aggravates diabetic complications and increases mortality from diabetes.DP is caused by diabetes-enhanced host immune-inflammatory responses to bacterial insult.In this study,we fo...Diabetes-associated periodontitis(DP)aggravates diabetic complications and increases mortality from diabetes.DP is caused by diabetes-enhanced host immune-inflammatory responses to bacterial insult.In this study,we found that persistently elevated CCL2 levels in combination with proinflammatory monocyte infiltration of periodontal tissues were closely related to DP.Moreover,inhibition of CCL2 by oral administration of bindarit reduced alveolar bone loss and increased periodontal epithelial thickness by suppressing periodontal inflammation.Furthermore,bindarit suppressed the infiltration of proinflammatory monocytes and altered the inflammatory properties of macrophages in the diabetic periodontium.This finding provides a basis for the development of an effective therapeutic approach for treating DP.展开更多
基金Acknowledgment This research was supported by grants from the Ministry of Science and Technology of China （2006CB943901, 2007CB948003） the National Natural Science Foundation of China （30600306, 30623003） Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences （2007KIP 101,2007KIP401）, Chinese Academy of Sciences.
文摘Dear Editor, Human embryonic stem （ES） cells possess the potential to differentiate into all the cell types of the human body and provide potential applications in regenerative medicine . However, the concerns of immune rejection hamper transplantation therapies using human ES cells. To avoid the complications of immune rejection, diverse methods, such as somatic nuclear transfer （also called therapeutic cloning） and fusion of somatic ceils with human ES ceils , have been attempted to produce patient-specific pluripotent stem cells. Most of these approaches have resulted in little success. The generation of human iPS cells （induced
基金Acknowledgements This study was supported in part by a grant from the Jiangsu Provincial Natural Science Foundation （No. 2006540）, Suchow University Young Natural Science Foundation and Key Project of Chinese Academy of Science （KSCX1-YW- 22-04）.
文摘There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B （NF-κB）, a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-κB activation in inflammatory bowel diseases （IBDs） increases risk of colorectal cancer （CRC） in the patients with the number of years of active disease. NF-κB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-κB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation （Cyclin D1）, angiogenesis （VEGF, IL-8, COX2）, and metastasis （MMP9）. These findings implicate NF-κB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-r,B subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-κB family, it will be a long time before the coming of targeting NF-κB in CRC therapy.
文摘Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and have diverse functions during development and organogenesis. BMPs play a major role in skeletal development and bone formation, and disruptions in BMP signaling cause a variety of skeletal and extraskeletal anomalies. Several knockout models have provided insight into the mechanisms responsible for these phenotypes. Proper bone formation requires the differentiation of osteoblasts from mesenchymal stem cell (MSC) precursors, a process mediated in part by BMP signaling. Multiple BMPs, including BMP2, BMP6, BMP7 and BMP9, promote osteoblastic differentiation of MSCs both in vitro and in vivo. BMP9 is one of the most osteogenic BMPs, yet it is a poorly characterized member of the BMP family. Several studies demonstrate that the mechanisms controlling BMP9-mediated osteogenesis differ from other osteogenic BMPs, but little is known about these specific mechanisms. Several pathways critical to BMP9-mediated osteogenesis are also important in the differentiation of other cell lineages, including adipocytes and chondrocytes. BMP9 has also demonstrated translational promise in spinal fusion and bone fracture repair. This review will summarize our current knowledge of BMP-mediated osteogenesis, with a focus on BMP9, by presenting recently completed work which may help us to further elucidate these pathways.
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.
文摘Dear Editor： The demonstration that four transcription factors, Oct4/Sox2/Myc/Klf4, can reprogram fibroblasts into ES-like cells or induced pluripotent stem cells （iPS cells） has generated tremendous interests not only in the field of stem cell biology, but also those related fields such as developmental biology and regenerative medicine [1-5]. The advance has greatly improved the prospects of generating patient specific pluripotent stem cells for therapeutic purposes without therapeutic cloning, an approach with formidable technical as well as ethical challenges. The conceptual breakthrough of the iPS strategy is quite obvious, demonstrating for the first time that the reprogramming of somatic nuclei can be achieved through a rational combination of transcription factors with defined regulatory activities, in contrast to the ill defined reprogramming power of unfertilized eggs. However, the application of the iPS strategy is so far limited to mouse fibroblasts carrying engineered selection markers [3, 4]. The need for selection using drug resistance or marker driven by Nanog-or Oct4-promoters would hamper not only its application in human therapy, but also any at- tempts to popularize this exciting experimental approach to other species such as primates. We reason that cells reprogrammed by Oct4/Sox2/Myc/Klf4 can be identified morphologically among the parental fibroblasts and the acquired pluripotent property should offer a growth advantage over their parental fibroblasts.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+9 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA14
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
文摘BACKGROUND Premature ovarian failure(POF)affects many adult women less than 40 years of age and leads to infertility.According to previous reports,various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF.Human embryonic stem cells(ES)provide an alternative source for mesenchymal stem cells(MSCs)because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics.Embryonic stem cell-derived mesenchymal stem cells(ES-MSCs)are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs.However,possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated.AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells(BMMSCs)in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure.METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF.Either human ES-MSCs or BMMSCs were transplanted into these mice.Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ESMSCs and/or BM-MSCs,we evaluated body weight,estrous cyclicity,folliclestimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation.Moreover,terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling,real-time PCR,Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation.Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor,insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function.RESULTS The human ES-MSCs significantly restored hormone s
文摘Vascular injury,remodeling,as well as angiogenesis,are the leading causes of coronary or cerebrovascular disease.The blood vessel functional imbalance trends to induce atherosclerosis,hypertension,and pulmonary arterial hypertension.As several genes have been identified to be dynamically regulated during vascular injury and remodeling,it is becoming widely accepted that several types of non-coding RNA,such as microRNAs(miRNAs)and long non-coding RNAs(lncRNAs),are involved in regulating the endothelial cell and vascular smooth muscle cell(VSMC)behaviors.Here,we review the progress of the extant studies on mechanistic,clinical and diagnostic implications of miRNAs and lncRNAs in vascular injury and remodeling,as well as angiogenesis,emphasizing the important roles of miRNAs and lncRNAs in vascular diseases.Furthermore,we introduce the interaction between miRNAs and lncRNAs,and highlight the mechanism through which lncRNAs are regulating the miRNA function.We envisage that continuous in-depth research of non-coding RNAs in vascular disease will have significant implications for the treatment of coronary or cerebrovascular diseases.
基金supported by the National Natural Science Foundation of China (91949209, 91749202, 92149301, 92168201)the National Key Research and Development Program of China (2018YFC2000100, 2020YFA0804000)+5 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000)the National Natural Science Foundation of China (81921006, 81625009, 82125011)the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221)the 14th Five-year Network Security and Informatization Plan of Chinese Academy of Sciences (WX145XQ0718)Informatization Plan of Chinese Academy of Sciences (CASWX2021SF-0301)the Milky Way Research Foundation (MWRF)
文摘Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and sirtuins(SIRTs).Among them,sirtuins are known as a protein family with versatile functions,such as metabolic control,epigenetic modification and lifespan extension.Therefore,by understanding how sirtuins regulate metabolic processes,we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation.Here,we review the biology of SIRT3,SIRT4,and SIRT5,known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix.First,we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation.Then,we will summarize the current knowledge about functional differences between SIRT3,SIRT4,and SIRT5 in metabolic control and integration in signaling networks.Finally,we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.
基金supported by the National Natural Science Foundation of China (81830004, 31922046, 31770057, 31722036, 31930016, 31870893)the Sanming Project of Medicine in Shenzhen (SZSM202011017)+5 种基金the National Key Research and Development Program of China (2018YFA0801401, 2019YFA0110800, 2018YFA0107703, 2019YFA0110000, 2020YFA0707800, 2020YFA0707600)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030403, XDA16010503)Beijing Municipal Science & Technology Commission (Z181100001318009)Beijing Advanced Innovation Center for Genomics at Peking Universitythe Peking-Tsinghua Center for Life Sciencesthe National Major Science & Technology Project for Control and Prevention of Major Infectious Diseases in China (2018ZX10301401)
文摘The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats(CRISPR) and programmable nucleases to make precise modifications to genetic material, has provided enormous opportunities to advance biomedical research and promote human health. The application of these technologies in basic biomedical research has yielded significant advances in identifying and studying key molecular targets relevant to human diseases and their treatment. The clinical translation of genome editing techniques offers unprecedented biomedical engineering capabilities in the diagnosis, prevention, and treatment of disease or disability. Here, we provide a general summary of emerging biomedical applications of genome editing, including open challenges. We also summarize the tools of genome editing and the insights derived from their applications, hoping to accelerate new discoveries and therapies in biomedicine.
基金We are grate to Xinglong Chen,Ziyi Zhao,Baohong Tian and all members from animal facility of the Yunnan Key Laboratory of Primate Biomedical Research for excellent animal welfare and husbandry.We thank Jing He for her technical assistance.The author would like to thank Gabriella Rudy for constructive criticism of the manuscript.This work was supported by the National Key Research and Development Program(2016YFA0101401)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)+2 种基金the National Key Research and Development Program(2018YFA0801403,2018YFC2000100)the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,91949209,81822018,91749123,81671377)Youth Innovation Promotion Association of CAS(2016093).
文摘Many human genetic diseases,including Hutchinson-Gilford progeria syndrome(HGPS),are caused by single point mutations.HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene.Base editors(BEs)composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions.Here,we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA(gRNA)targeting the LMNA gene via microinjection into monkey zygotes.Five out of six newborn monkeys carried the mutation specifically at the target site.HGPS monkeys expressed the toxic form of lamin A,progerin,and recapitulated the typical HGPS phenotypes including growth retardation,bone alterations,and vascular abnormalities.Thus,this monkey model genetically and clinically mimics HGPS in humans,demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.
文摘GUoma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase （IDH） mutations in up to 80% lower grade gUomas （LGG） and in 76% secondary gUoblastomas （GBM）. IDH mutations are also seen in 10%-20% of acute myeloid leukemia （AML）. In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells （pre-LSCs） stage, whereas mutations in genes propa- gating oncogenic signal are late events in leukemia. IDH mutations are also early events in gUoma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in gUoma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD# as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK#, FIPIL1, or FUBP1 collaborate with IDH mutations to negatively affect patients＇ survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4, at gen- etic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and gUoma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premaUgnant stem cells to gUoma.
基金This work was supported by the National Key Research and Development Program of China(2017YFA0105804)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+8 种基金the National Key Research and Development Program of China(2018YFC2000100,2017YFA0103304,2017YFA0102802,2018YFA0107203)the National Natural Science Foundation of China(81670897,81625009,91749202.81861168034,81921006,31671429,91949209,91749123,81671377,81822018,81870228,81922027,81701388,81601233)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Bejing Natural Science Foun-dation(Z190019)Bejing Municipal Commission of Health and Family Planning(PXM2018026283_000002)Advanced Innovation Center for Human Brain Protection(3500-1192012)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08),Youth Innovation Promotion Association of CAS(2016093)the State Key Laboratory of Membrane Biology and the State Key Laboratory of Stem Cell and Reproductive Biology.
文摘Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
基金This study was supported by the National Basic Research Program of China （2012CBA01302, 2010CB945400）, the National Natural Science Foundation of China （31171398, 81271265, 81425016）, the Key Scientific and Technological Projects of Guangdong Province （2007A032100003）, the Natural Science Foundation of Guangdong Province （ S2013030013305 ）, the Key Scientific and Technological Program of Guangzhou City （201400000003-3, 201300000089, 2010U1-E00551 ） and Guangdong Department of Science ＆ Technology Translational Medicine Center grant （2011A080300002）.
文摘One important aspect of mesenchymal stromal cells （MSCs）-mediated immunomodulation is the recruitment and induction of regulatory T （Treg） cells. However, we do not yet know whether MSCs have similar effects on the other subsets of Treg cells. Herein, we studied the effects of MSCs on CD8＋CD28- Treg cells and found that the MSCs could not only increase the proportion of CD8＋CD28- T cells, but also enhance CD8＋CD28-T cells＇ ability of hampering naive CD4＋ T-cell proliferation and activation, decreasing the production of IFN-γ by activated CD4＋ T cells and inducing the apoptosis of activated CD4＋ T cells. Mechanistically, the MSCs affected the functions of the CD8＋CD28- T cells partially through moderate upregulating the expression of IL-10 and FasL. The MSCs had no distinct effect on the shift from CD8＋CD28＋ T cells to CD8＋CD28- T cells, but did increase the proportion of CD8＋CD28- T cells by reducing their rate of apoptosis. In summary, this study shows that MSCs can enhance the regulatory function of CD8＋CD28- Treg cells, shedding new light on MSCs-mediated immune regulation.
基金supported by the National Natural Science Foundation of China(NSFC)[81672119 and 81725010 to W.Z.]W Z is a scholar of‘the National Science Fund for Distinguished Young Scholars’(NSFC)[81725010]+4 种基金the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to P.H.)Ministry of Science and Technology of China(2017YFA0102700 to P.H.)National Natural Science Foundation of China(32170804 to PH)P.H.the fellowship of China Postdoctoral Science Foundation(2021TQ0207,2021M702184 to J.S.)the‘Basic research project of Shanghai Sixth People’s Hospital’(ynqn202102 to J.S.)。
文摘Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
文摘The percentage of elderly people in the world is increasing at an unprecedented pace;so it is in China, which has the world s largest population and a high ratio of the seniors (aged 60 and above) to working-age adults. The growing elderly population is presenting a major social challenge. Accordingly, it is not only imperative as a national strategic demand but also promises great scientific values to understand the biological process of aging, explore the mystery of healthy aging, delay the aging process, and treat the age-related diseases. This Perspective summarizes past and present advances of the basic and translational aging research in China and offers perspectives on future endeavors in this area.
基金supported by the National Key Research and Development Program of China,Nos.2017YFE0122900(to BH),2019YFA0110800(to WL),2019YFA0903802(to YW),2021YFA1101604(to LW),2018YFA0108502(to LF),and 2020YFA0804003(to JW)the National Natural Science Foundation of China,Nos.31621004(to WL,BH)and 31970821(to YW)+1 种基金CAS Project for Young Scientists in Basic Research,No.YSBR-041(to YW)Joint Funds of the National Natural Science Foundation of China,No.U21A20396(to BH)。
文摘Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.
基金supported by the National Key Research-and Development Program of China(2022YFA1103700)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA160000c0)+9 种基金the National Key Research and Development Program of China(2020YFAOB04000,2020YFA0112200,2021YFF1201005,2022YFA1103B00),the STI2030-Major Projects(20212D0202400)the National Natural Science Foundation af China(Grant Nos 81921006,82125011,92149301,9216820191949209,92049304,92049116,32121001,82192863,82122024.82071588,32000500,31900523,82201714,82271600,82201727)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019)China Postdoctoral Science Foundation(2022M712216)кC.Wong Education Foundation(GJTD-2019-06 GTD-2019-08)the lot Proje for Publie Welfare Development and Reform of Beijing-affiliated Medical Restarch Institutes(11000022T000000461062)Young Elte Scientists Sponsorship Progran by CAST YESS20000012,YES520210002)Yout Innovation Promotion Association of CAS(E1CAZWO-401,2022083)the Tencent Foundation(2021-1045)the Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CAS-WX2021SF-0101,CAS-WX2022SDC-XK14)Strategic Collaborative Research Program of the Ferring Institute of ReproductiveMedicine,Grant No.FIRMC180305。
文摘The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
文摘Dear Editor： Gao et al. published data in Nature Biotechnology （Nat Biotechnol. 2016 May 2） showing that DNA-guided genome editing using the Natronobacterium gregoryi Argonaute （NgAgo） protein targeted 47 mammalian genomic loci with a 100% success rate and an efficiency of 21.3%-41.3% at various targets. This report led us to test NgAgo＇s utility in various cells and organisms such as mouse and zebrafish for gene editing.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81873713,81670984,81873829,and 81700959)the International Cooperation Project of Science and Technology in Guangdong Province(Grant No.2016B050502008).
文摘Diabetes-associated periodontitis(DP)aggravates diabetic complications and increases mortality from diabetes.DP is caused by diabetes-enhanced host immune-inflammatory responses to bacterial insult.In this study,we found that persistently elevated CCL2 levels in combination with proinflammatory monocyte infiltration of periodontal tissues were closely related to DP.Moreover,inhibition of CCL2 by oral administration of bindarit reduced alveolar bone loss and increased periodontal epithelial thickness by suppressing periodontal inflammation.Furthermore,bindarit suppressed the infiltration of proinflammatory monocytes and altered the inflammatory properties of macrophages in the diabetic periodontium.This finding provides a basis for the development of an effective therapeutic approach for treating DP.
