Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attem...Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.展开更多
The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological ...The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological functions.However,how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear.In this study,we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium(Slc16a1IKO mice)and investigated the functions of MCT1 in the gut.When fed a high-fat diet,Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity,while Slc16a1IKO female mice only had increased adiposity.Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways,together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha(TNFα)and C-C motif chemokine ligand 2(CCL2).Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro.The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo.Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine.In addition,treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice.Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein.The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota.In conclusion,our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.展开更多
The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In ...The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.展开更多
Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts;however, their efficacy needs to be enhanced. Here we tested th...Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts;however, their efficacy needs to be enhanced. Here we tested the hypotheses that the combination of decellularized porcine small intestinal submucosal extracellular matrix (SIS-ECM) with hCVPCs, hCMs, or dual of them (Mix, 1:1) could provide better therapeutic effects than the SIS alone, and dual hCVPCs with hCMs would exert synergic effects in cardiac repair. The data showed that the SIS patch well supported the growth of hCVPCs and hCMs. Epicardially implanted SIS-hCVPC, SIS-hCM, or SIS-Mix patches at 7-day post-myocardial infarction significantly ameliorated functional worsening, ventricular dilation and scar formation at 28- and 90-day post-implantation in C57/B6 mice, whereas the SIS only mildly improved function at 90-day post-implantation. Moreover, the SIS and SIS-cell patches improved vascularization and suppressed MI-induced cardiomyocyte hypertrophy and expression of Col1 and Col3, but only the SIS-hCM and the SIS-Mix patches increased the ratio of collagen III/I fibers in the infarcted hearts. Further, the SIS-cell patches stimulated cardiomyocyte proliferation via paracrine action. Notably, the SIS-Mix had better improvements in cardiac function and structure, engraftments, and cardiomyocyte proliferation. Proteomic analysis showed distinct biological functions of exclusive proteins secreted from hCVPCs and hCMs, and more exclusive proteins secreted from co-cultivated hCVPCs and hCMs than mono-cells involving in various functional processes essential for infarct repair. These findings are the first to demonstrate the efficacy and mechanisms of mono- and dual-hCVPC- and hCM-seeding SIS-ECM for repair of infarcted hearts based on the side-by-side comparison.展开更多
Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer develop...Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.展开更多
Dear Editor,Myocardial injury following ischemia/reperfusion(I/R)is a common clinical scenario in patients suffering from ischemic heart disease(Hausenloy et al.,2016).The involvement of proteins and signaling pathway...Dear Editor,Myocardial injury following ischemia/reperfusion(I/R)is a common clinical scenario in patients suffering from ischemic heart disease(Hausenloy et al.,2016).The involvement of proteins and signaling pathways is well studied in myocardial I/R injury and protection(Hausenloy et al.,2016;Yang et al.,2012),however,more than 98%of the transcriptional output in mammals are noncoding RNAs(ncRNAs).These products range from short microRNAs(miRNAs)to long noncoding RNAs(lncRNAs,Das et al.,2018)and modulate critical pathophysiologic mechanisms,such as apoptosis,oxidative stress,Ca2+overload and inflammation,during myocardial I/R injury and protection(Das et al.,2018).展开更多
Ca^(2+) signaling is critical for heart development;however,the precise roles and regulatory pathways of Ca^(2+) transport proteins in cardiogenesis remain largely unknown.Sodium-calcium exchanger 1(Ncx1)is responsibl...Ca^(2+) signaling is critical for heart development;however,the precise roles and regulatory pathways of Ca^(2+) transport proteins in cardiogenesis remain largely unknown.Sodium-calcium exchanger 1(Ncx1)is responsible for Ca^(2+) efflux in cardiomyocytes.It is involved in cardiogenesis,while the mechanism is unclear.Here,using the forward genetic screening in zebrafish,we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene(mutant^(LDD353)/ncx1h^(L154P))that led to smaller hearts with reduced heart rate and weak contraction.Mechanistically,the number of ventricular but not atrial cardiomyocytes was reduced in ncx1h^(L154P) zebrafish.These defects were mimicked by knockdown or knockout of ncx1h.Moreover,ncx1h^(L154P) had cytosolic and mitochondrial Ca^(2+) overloading and Ca^(2+) transient suppression in cardiomyocytes.Furthermore,ncx1h^(L154P) and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions,while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes.These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish,and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.展开更多
Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study ...Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.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
Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenviron...Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenvironment of triple negative breast cancer(TNBC)compared with other subtypes of breast cancer remain elusive.Therefore,we aimed to depict and compare the immune landscape among TNBC,human epidermal growth factor receptor 2-positive(HER2^(+))breast cancer,and luminal-like breast cancer.Methods:Single-cell RNA sequencing(scRNA-seq)was performed on CD45^(+)immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes.By analyzing the scRNA-seq data,immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC,human HER2^(+)breast cancer,and luminal-like breast cancer.Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment.Results:ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified.A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2^(+)or luminal-like breast cancer,which was characterized by higher proportions of regulatory T cells(Tregs)and exhausted CD8+T cells and accompanied by more abundant plasma cells.Tregs and exhausted CD8+T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores.Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC.Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC.Based on the T cell-B cell crosstalk,a prognostic signaturewas established that could effectively predict the prognosis status for patients with TNBC.Additionally,it was found that TNBC had a higher proportion of cytotoxic natural killer(NK)cells,whereas HER2^(+)or luminal-like breast cancer lost this feature,suggesting thatHER2^(+)or luminal-like breast cancer,but not TNBC,may benefit from NK-based immunotherapy.Conclusions:This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC,which provides better prognostic information and effective therapeutic targets for breast cancer.展开更多
Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytoki...Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytokines production,such as IL-5 and IL-13[1].展开更多
Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monito...Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.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
Adipose tissues are essential for actively regulating systemic energy balance,glucose homeostasis,immune responses,reproduction,and longevity.Adipocytes maintain dynamic metabolic needs and possess heterogeneity in en...Adipose tissues are essential for actively regulating systemic energy balance,glucose homeostasis,immune responses,reproduction,and longevity.Adipocytes maintain dynamic metabolic needs and possess heterogeneity in energy storage and supply.Overexpansion of adipose tissue,especially the visceral type,is a high risk for diabetes and other metabolic diseases.Changes in adipocytes,hypertrophy or hyperplasia,contribute to the remodeling of obese adipose tissues,accompanied by abundant immune cell accumulation,decreased angiogenesis,and aberrant extracellular matrix deposition.The process and mechanism of adipogenesis are well known,however,adipose precursors and their fate decision are only being defined with recent information available to decipher how adipose tissues generate,maintain,and remodel.Here,we discuss the key findings that identify adipose precursors phenotypically,with special emphasis on the intrinsic and extrinsic signals in instructing and regulating the fate of adipose precursors under pathophysiological conditions.We hope that the information in this review lead to novel therapeutic strategies to combat obesity and related metabolic diseases.展开更多
Correction:Cell Regen 12,13(2023).https://doi.org/10.1186/s13619-023-00157-8.Following publication of the original article(Ye et al.2023),the authors reported that the“Competing inter-ests”section needed to be updat...Correction:Cell Regen 12,13(2023).https://doi.org/10.1186/s13619-023-00157-8.Following publication of the original article(Ye et al.2023),the authors reported that the“Competing inter-ests”section needed to be updated.The original version was:The authors declare no competing interests.展开更多
OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the ...OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown.Here,we showed intestinal ILC3s marked as an OX40L high population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1–/–mice.All ILC3 subsets expressed OX40L,and NCR–ILC3s were the most abundant source of OX40L.The expression of OX40L in ILC3s could be upregulated during inflammation.In addition to tumor necrosis factor(TNF)-like cytokine 1A(TL1A),which has been known as a trigger for OX40L,we found that Poly(I:C)representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner.Furthermore,we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s.Intestinal regulatory T cells(Tregs),most of which expressed OX40,had defective expansion in chimeric mice,in which ILC3s were specifically deficient for OX40L expression.Consistently,co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine,which suggests the close interaction between ILC3s and Tregs.Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40–OX40L signaling,which is crucial for the homeostasis of intestinal Tregs.展开更多
Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells(MSCs).However,the biological function of chaperone-mediated autophagy(CMA)in MSCs remains elusive.Here,we found th...Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells(MSCs).However,the biological function of chaperone-mediated autophagy(CMA)in MSCs remains elusive.Here,we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ(IFN-γ)and tumor necrosis factor-α(TNF-α).In addition,suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2(LAMP-2A)in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation,and as expected,LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation.This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10(CXCL10),which recruits inflammatory cells,especially T cells,to MSCs,and inducible nitric oxide synthase(iNOS),which leads to the subsequent inhibition of T cell proliferation via nitric oxide(NO).Mechanistically,CMA inhibition dramatically promoted IFN-γplus TNF-α-induced activation of NF-κB and STAT1,leading to the enhanced expression of CXCL10 and iNOS in MSCs.Furthermore,we found that IFN-γplus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs.More interestingly,CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury.Taken together,our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines nd highlighted a previously unknown function of CMA.展开更多
T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understoo...T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.展开更多
Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a me...Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a member of the IκB family,is overexpressed in CRC and promotes tumorigenicity.Here,we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling.Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling.Moreover,our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential forβ-catenin transcriptional activity in CRC cells.Interestingly,Wnt3a increases the level and nuclear translocation of Bcl-3,which binds directly toβ-catenin and enhances the acetylation ofβ-catenin at lysine 49(Ac-K49-β-catenin)and transcriptional activity.Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups fromβ-catenin,thus interrupting Wnt/β-catenin activity.In CRC clinical specimens,Bcl-3 expression negatively correlates with the overall survival of CRC patients.A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin.Collectively,our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin,which serves as a promising therapeutic target for CRC.展开更多
Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcripti...Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcriptional heterogeneity of MCs was rarely studied.In this study,we illustrated the transcriptional heterogeneity of MCs with different perspectives by using publicly available single-cell dataset GSE109774.Specifically,MCs are transcriptionally different from other cell types,and ligand-receptor interactions of different cells with MCs vary.Re-clustering of MCs identified five distinct subclusters.The heterogeneity of MCs in tissues was reflected by MC coverage,various distribution of MC subclusters,and ligand-receptor interactions of MCs and parenchymal cells.The transcriptomic diversity of MCs revealed in this article will help facilitate further research into MCs.展开更多
基金This work was supported by grants from National Natural Science Foundation of China(81830078,82071868,32370892)Science and Technology Commission of Shanghai Municipality(23141901200)+2 种基金Health Commission of Shanghai Municipality(2022JC029)Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiaotong University School of Medicine(2022LHA11)Shanghai Key Laboratory of Orthopedic Implant(No.KFKT202206).
文摘Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.
基金funded by the National Natural Science Foundation of China(32230047 to Y.C.)the Shanghai Municipal Science and Technology Major Project(to Y.C.).
文摘The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological functions.However,how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear.In this study,we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium(Slc16a1IKO mice)and investigated the functions of MCT1 in the gut.When fed a high-fat diet,Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity,while Slc16a1IKO female mice only had increased adiposity.Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways,together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha(TNFα)and C-C motif chemokine ligand 2(CCL2).Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro.The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo.Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine.In addition,treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice.Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein.The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota.In conclusion,our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.
基金supported by the National Key Research and Development Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang)the General Program of the National Natural Science Foundation of China(Nos.81470316 and 81670094 to Xiaojian Sun,No.81972339 to Zhe Bao Wu,Nos.81570122 and 81770205 to Jinyan Huang,Nos.81670122 and 81970150 to Lan Wang)+5 种基金the National Research Center for Translational Medicine(Shanghai)grant(No.NRCTM(SH)-2019-05 to Zhe Bao Wu)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No.20152506 to Xiaojian Sun)Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun)Innovative Research Team of High-level Local Universities in Shanghai(to Weili Zhao and Xiaojian Sun)the Samuel Waxman Cancer Research Foundationthe Shanghai Guangci Translational Medical Research Development Foundation.
文摘The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.
文摘Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts;however, their efficacy needs to be enhanced. Here we tested the hypotheses that the combination of decellularized porcine small intestinal submucosal extracellular matrix (SIS-ECM) with hCVPCs, hCMs, or dual of them (Mix, 1:1) could provide better therapeutic effects than the SIS alone, and dual hCVPCs with hCMs would exert synergic effects in cardiac repair. The data showed that the SIS patch well supported the growth of hCVPCs and hCMs. Epicardially implanted SIS-hCVPC, SIS-hCM, or SIS-Mix patches at 7-day post-myocardial infarction significantly ameliorated functional worsening, ventricular dilation and scar formation at 28- and 90-day post-implantation in C57/B6 mice, whereas the SIS only mildly improved function at 90-day post-implantation. Moreover, the SIS and SIS-cell patches improved vascularization and suppressed MI-induced cardiomyocyte hypertrophy and expression of Col1 and Col3, but only the SIS-hCM and the SIS-Mix patches increased the ratio of collagen III/I fibers in the infarcted hearts. Further, the SIS-cell patches stimulated cardiomyocyte proliferation via paracrine action. Notably, the SIS-Mix had better improvements in cardiac function and structure, engraftments, and cardiomyocyte proliferation. Proteomic analysis showed distinct biological functions of exclusive proteins secreted from hCVPCs and hCMs, and more exclusive proteins secreted from co-cultivated hCVPCs and hCMs than mono-cells involving in various functional processes essential for infarct repair. These findings are the first to demonstrate the efficacy and mechanisms of mono- and dual-hCVPC- and hCM-seeding SIS-ECM for repair of infarcted hearts based on the side-by-side comparison.
基金National Natural Science Foundation of China,Grant/Award Numbers:81902386,81972869,82002479The Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211065,BK20200179+2 种基金China Postdoctoral Science Foundation,Grant/Award Number:2021M700547Youth Talent Science and Technology Project of Changzhou Health Commission,Grant/Award Number:QN202103The open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University,China,Grant/Award Number:KF-202203。
文摘Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.
基金supported by the National Natural Science Foundation of China (81770402)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010201)National Key R&D Program of China (2017YFA 0103700, 2016YFC1301204)
文摘Dear Editor,Myocardial injury following ischemia/reperfusion(I/R)is a common clinical scenario in patients suffering from ischemic heart disease(Hausenloy et al.,2016).The involvement of proteins and signaling pathways is well studied in myocardial I/R injury and protection(Hausenloy et al.,2016;Yang et al.,2012),however,more than 98%of the transcriptional output in mammals are noncoding RNAs(ncRNAs).These products range from short microRNAs(miRNAs)to long noncoding RNAs(lncRNAs,Das et al.,2018)and modulate critical pathophysiologic mechanisms,such as apoptosis,oxidative stress,Ca2+overload and inflammation,during myocardial I/R injury and protection(Das et al.,2018).
基金supported by grants from the National Natural Science Foundation of China(81520108004,81470422)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010201)+1 种基金National Key R&D Program of China(2017YFA 0103700,2016YFC1301204)to H.-T.Y.Shanghai Natural Science Foundation(17ZR1435500)to J.H。
文摘Ca^(2+) signaling is critical for heart development;however,the precise roles and regulatory pathways of Ca^(2+) transport proteins in cardiogenesis remain largely unknown.Sodium-calcium exchanger 1(Ncx1)is responsible for Ca^(2+) efflux in cardiomyocytes.It is involved in cardiogenesis,while the mechanism is unclear.Here,using the forward genetic screening in zebrafish,we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene(mutant^(LDD353)/ncx1h^(L154P))that led to smaller hearts with reduced heart rate and weak contraction.Mechanistically,the number of ventricular but not atrial cardiomyocytes was reduced in ncx1h^(L154P) zebrafish.These defects were mimicked by knockdown or knockout of ncx1h.Moreover,ncx1h^(L154P) had cytosolic and mitochondrial Ca^(2+) overloading and Ca^(2+) transient suppression in cardiomyocytes.Furthermore,ncx1h^(L154P) and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions,while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes.These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish,and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.
基金supported by the National Natural Science Foundation of China(Grant Nos.31871329,1670066,81872888,and 81821005)Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)+2 种基金the Key New Drug Creation and Manufacturing Program of China(Grant No.2018ZX09711002-004)the Special Project on Precision Medicine under the National Key R&D Program(Grant No.SQ2017YFSF090210)the K.C.Wong Education Foundation。
文摘Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.
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National Natural Science Foundation of China,Grant/Award Numbers:82072937,82072897,82002773Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant,Grant/Award Number:20172007Science and Technology Commission of Shanghai Municipality Shanghai Sailing Program,Grant/Award Number:21YF1427400。
文摘Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenvironment of triple negative breast cancer(TNBC)compared with other subtypes of breast cancer remain elusive.Therefore,we aimed to depict and compare the immune landscape among TNBC,human epidermal growth factor receptor 2-positive(HER2^(+))breast cancer,and luminal-like breast cancer.Methods:Single-cell RNA sequencing(scRNA-seq)was performed on CD45^(+)immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes.By analyzing the scRNA-seq data,immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC,human HER2^(+)breast cancer,and luminal-like breast cancer.Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment.Results:ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified.A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2^(+)or luminal-like breast cancer,which was characterized by higher proportions of regulatory T cells(Tregs)and exhausted CD8+T cells and accompanied by more abundant plasma cells.Tregs and exhausted CD8+T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores.Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC.Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC.Based on the T cell-B cell crosstalk,a prognostic signaturewas established that could effectively predict the prognosis status for patients with TNBC.Additionally,it was found that TNBC had a higher proportion of cytotoxic natural killer(NK)cells,whereas HER2^(+)or luminal-like breast cancer lost this feature,suggesting thatHER2^(+)or luminal-like breast cancer,but not TNBC,may benefit from NK-based immunotherapy.Conclusions:This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC,which provides better prognostic information and effective therapeutic targets for breast cancer.
基金This work was supported by grants 2020YFA0509103 and 2019YFA0802502 to JQ from the Ministry of Science and Technology of China,grants 32022027 and 31970860 to JQ from the National Natural Science Foundation of China and grants 22ZR1481800 and 20ZR1466900 to JQ from Shanghai Science and Technology Committee(STCSM).
文摘Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytokines production,such as IL-5 and IL-13[1].
基金supported by the Lingang Laboratory (LG202103-02-03)National Natural Science Foundation of China (82173832,81973345 and 82104199)+2 种基金the State Key Laboratory of Drug Research (SIMM2205KF-05)Science and Technology Commission of Shanghai Municipality (22ZR1474400)“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”,Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020111).
文摘Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.
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)+14 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(2019ACA141)the Science and Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Sichuan Province(2023NSFSC0003)Yunnan Fundamental Research Project(202201AS070080)the State Key Laboratory of Membrane Biology。
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.
基金supported by grants from the National Key R&D Program of China(2022YFA0807300,2018YFA0107500)the Scientific Innovation Project of the Chinese Academy of Sciences(XDA16020403)the National Natural Science Foundation of China(31961133024,32070872,81861138015,81930085 and 81571612).
文摘Adipose tissues are essential for actively regulating systemic energy balance,glucose homeostasis,immune responses,reproduction,and longevity.Adipocytes maintain dynamic metabolic needs and possess heterogeneity in energy storage and supply.Overexpansion of adipose tissue,especially the visceral type,is a high risk for diabetes and other metabolic diseases.Changes in adipocytes,hypertrophy or hyperplasia,contribute to the remodeling of obese adipose tissues,accompanied by abundant immune cell accumulation,decreased angiogenesis,and aberrant extracellular matrix deposition.The process and mechanism of adipogenesis are well known,however,adipose precursors and their fate decision are only being defined with recent information available to decipher how adipose tissues generate,maintain,and remodel.Here,we discuss the key findings that identify adipose precursors phenotypically,with special emphasis on the intrinsic and extrinsic signals in instructing and regulating the fate of adipose precursors under pathophysiological conditions.We hope that the information in this review lead to novel therapeutic strategies to combat obesity and related metabolic diseases.
文摘Correction:Cell Regen 12,13(2023).https://doi.org/10.1186/s13619-023-00157-8.Following publication of the original article(Ye et al.2023),the authors reported that the“Competing inter-ests”section needed to be updated.The original version was:The authors declare no competing interests.
基金This study was supported by grants 2015CB943400 and 2014CB943300 from the Ministry of Science and Technology of Chinagrant XDB19000000 from the“Strategic priority research program of the Chinese Academy of Sciences”+1 种基金grants 91542102 and 31570887 from the National Natural Science Foundation of ChinaChina's Youth 1000 Talent Program to Q.J.
文摘OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown.Here,we showed intestinal ILC3s marked as an OX40L high population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1–/–mice.All ILC3 subsets expressed OX40L,and NCR–ILC3s were the most abundant source of OX40L.The expression of OX40L in ILC3s could be upregulated during inflammation.In addition to tumor necrosis factor(TNF)-like cytokine 1A(TL1A),which has been known as a trigger for OX40L,we found that Poly(I:C)representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner.Furthermore,we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s.Intestinal regulatory T cells(Tregs),most of which expressed OX40,had defective expansion in chimeric mice,in which ILC3s were specifically deficient for OX40L expression.Consistently,co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine,which suggests the close interaction between ILC3s and Tregs.Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40–OX40L signaling,which is crucial for the homeostasis of intestinal Tregs.
基金supported by the Ministry of Science and Technology of China(2015CB943300 and 2011CB966200)the National Natural Science Foundation of China(81873447 and 81670540)+1 种基金The Program of Science and Technology Commission of Shanghai Municipality(19ZR1409200 and 19ZR1430900)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01040000).
文摘Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells(MSCs).However,the biological function of chaperone-mediated autophagy(CMA)in MSCs remains elusive.Here,we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ(IFN-γ)and tumor necrosis factor-α(TNF-α).In addition,suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2(LAMP-2A)in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation,and as expected,LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation.This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10(CXCL10),which recruits inflammatory cells,especially T cells,to MSCs,and inducible nitric oxide synthase(iNOS),which leads to the subsequent inhibition of T cell proliferation via nitric oxide(NO).Mechanistically,CMA inhibition dramatically promoted IFN-γplus TNF-α-induced activation of NF-κB and STAT1,leading to the enhanced expression of CXCL10 and iNOS in MSCs.Furthermore,we found that IFN-γplus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs.More interestingly,CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury.Taken together,our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines nd highlighted a previously unknown function of CMA.
基金supported by grants from the National Key R&D Program of China(2018YFA0107201,2018YFA0902703)the National Natural Science Foundation of China(82030041,81770567)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39030300)the Program of Shanghai Academic/Technology Research Leader(20XD1424600)the Key Research Program of the Chinese Academy of Sciences(CAS)(KFZD-SW-216)the Thousand Young Talents Plan of Chinathe CAS Key Laboratory of Tissue Microenvironment and Tumor.
文摘T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.
基金funded by the National Program on Key Research(2018YFA0107500,2016YFC1302400)National Basic Research Program(2014CB541904 and 2014CB943600)+3 种基金National Natural Science Foundation of China(91742113,31570902,81702950,81772798,91949102 and 81771752)Natural Science Foundation of Shanghai(14ZR1426300,18ZR1424400,18ZR1446400,18431902700)China Postdoctoral Science Foundation(2017M611633)Guangzhou Key Medical Discipline Construction Project Fund.
文摘Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a member of the IκB family,is overexpressed in CRC and promotes tumorigenicity.Here,we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling.Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling.Moreover,our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential forβ-catenin transcriptional activity in CRC cells.Interestingly,Wnt3a increases the level and nuclear translocation of Bcl-3,which binds directly toβ-catenin and enhances the acetylation ofβ-catenin at lysine 49(Ac-K49-β-catenin)and transcriptional activity.Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups fromβ-catenin,thus interrupting Wnt/β-catenin activity.In CRC clinical specimens,Bcl-3 expression negatively correlates with the overall survival of CRC patients.A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin.Collectively,our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin,which serves as a promising therapeutic target for CRC.
基金supported in part by the National Key Research and Development Program of China(2019YFA0802700,2017YFA0103700)the National Natural Science Foundation of China(91739301,91339205,81130005)。
文摘Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcriptional heterogeneity of MCs was rarely studied.In this study,we illustrated the transcriptional heterogeneity of MCs with different perspectives by using publicly available single-cell dataset GSE109774.Specifically,MCs are transcriptionally different from other cell types,and ligand-receptor interactions of different cells with MCs vary.Re-clustering of MCs identified five distinct subclusters.The heterogeneity of MCs in tissues was reflected by MC coverage,various distribution of MC subclusters,and ligand-receptor interactions of MCs and parenchymal cells.The transcriptomic diversity of MCs revealed in this article will help facilitate further research into MCs.