N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis a...N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.展开更多
In this Editorial review,we would like to focus on a very recent discovery showing the global autosomal gene regulation by Y-and inactivated X-chromosomal transcription factors,zinc finger gene on the Y chromosome(ZFY...In this Editorial review,we would like to focus on a very recent discovery showing the global autosomal gene regulation by Y-and inactivated X-chromosomal transcription factors,zinc finger gene on the Y chromosome(ZFY)and zinc finger protein X-linked(ZFX).ZFX and ZFY are both zinc-finger proteins that encode general transcription factors abundant in hematopoietic and embryonic stem cells.Although both proteins are homologs,interestingly,the regulation of self-renewal by these transcriptional factors is almost exclusive to ZFX.This fact implies that there are some differential roles between ZFX and ZFY in regulating the maintenance of self-renewal activity in stem cells.Besides the maintenance of stemness,ZFX overexpression or mutations may be linked to certain cancers.Although cancers and stem cells are double-edged swords,there is no study showing the link between ZFX activity and the telomere.Thus,stemness or cancers with ZFX may be linked to other molecules,such as Oct4,Sox2,Klf4,and others.Based on very recent studies and a few lines of evidence in the past decade,it appears that the ZFX is linked to the canonical Wnt signaling,which is one possible mechanism to explain the role of ZFX in the self-renewal of stem cells.展开更多
AIM： To identify cancer stern cells （CSCs） in human gallbladder carcinomas （GBCs）. METHODS： Primary GBC cells were cultured under serum-free conditions to produce floating spheres. The stem-cell properties of th...AIM： To identify cancer stern cells （CSCs） in human gallbladder carcinomas （GBCs）. METHODS： Primary GBC cells were cultured under serum-free conditions to produce floating spheres. The stem-cell properties of the sphere-forming cells, including self-renewal, differentiation potential, chemoresistance and tumorigenicity, were determined in vitro or in vivo. Cell surface expression of CD133 was investigated in primary tumors and in spheroid cells using flow cytometry. The sphere-colony-formation ability and tumorigenicity of CD133＋ cells were assayed.floating spheroids were generated from primary GBC cells, and these sphere-forming cells could generate new progeny spheroids in serum-free media. Spheroid cells were differentiated under serum-containing conditions with downregulation of the stem cell markers Oct-4, Nanog, and nestin （P 〈 0.05）. The differentiated cells showed lower spheroid-colony-formation ability than the original spheroid cells （P 〈 0.05）. Spheroid ceils were more resistant to chemotherapeutic reagents than the congenetic adherent cells （P 〈 0.05）. Flow cytometry showed enriched CD133＋ population in sphereforming cells （P 〈 0.05）. CD133＋ cells possessed high colony-formation ability than the CD133 population （P 〈 0.01）. CD133＋ cells injected into nude mice revealed higher tumorigenicity than their antigen-negative counterparts （P 〈 0.05）. CONCLUSION： CD133 may be a cell surface marker for CSCs in GBC.展开更多
AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （2...AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （20, 40, 80, 160, 200 ng/mL） in serum-free medium for 24 h. Cell proliferation was measured by Brdu incorporation analysis; untreated WB-F344 cells were taken as controls. After treatment with Wnt3a （160 ng/mL） for 24 h, subcellular localization and protein expression of p-catenin in WB-F344 cells treated and untreated with Wnt3a were examined by immunofluorescence staining and Western blot analysis. CyclinD1 mRNA expression was determined by semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR）. The mRNA levels of some phenotypic markers （AFP, CK-19, ALB） and two hepatic nuclear factors （HNF-4, HIVF-6） were measured by RT-PCR. Expressions of CK-19 and AFP protein were detected by Western blot analysis. RESULTS： Wnt3a promoted proliferation of WB-F344 cells. Stimulation of WB-F344 cells with recombinant Wnt3a resulte^l in accumulation of the transcriptional activator β-catenin, together with its translocation into the nuclei, and up-regulated typical Wnt target gene CyclinD1. After 3 d of Wnt3a treatment in the absence of serum, WB-F344 cells retained their bipotential to express several specific phenotypic markers of hepatocytes and cholangiocytes, such as AFP and CK-19, following activation of the canonical Wnt signaling pathway. CONCLUSION： The canonical Wnt signaling pathway promotes proliferation and self-renewal of rat hepatic oval cells.展开更多
A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigen...A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigenetic processes such as DNA methylation and chromatin remodeling. Several cytokines/growth factors have been identified as critical ES cell regulators. However, there is a gap in our knowledge of the intracellular signaling pathways linking extracellular signals to transcriptional regulation in ES cells. This short review discusses the physiological role of Shp2, a cytoplasmic tyro- sine phosphatase, in the molecular switch governing ES cell self-renewal versus differentiation. Shp2 promotes ES cell differentiation, mainly through bi-directional modulation of Erk and Stat3 pathways. Deletion of Shp2 in mouse ES cells results in more efficient self-renewal. This observation provides the impetus to develop Shp2 inhibitors for maintenance and amplification of ES cells in culture.展开更多
BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different C...BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.展开更多
Cancer stem cells(CSCs)possess self-renewal and differentiation potential,which may be related to recurrence,metastasis,and radiochemotherapy resistance during tumor treatment.Understanding the mechanisms via which CS...Cancer stem cells(CSCs)possess self-renewal and differentiation potential,which may be related to recurrence,metastasis,and radiochemotherapy resistance during tumor treatment.Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span.Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics.This review summarizes the relationship between CSCs and amino acid metabolism,and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal,survival and stemness.The ultimate goal is to identify new targets and research directions for elimination of CSCs.展开更多
The origin of macrophages has been considered since several decades to be a continuum from bone marrow （BM） to tissue via monocytes as precursors. The development of new tools such as genetic lineage tracing,parabio...The origin of macrophages has been considered since several decades to be a continuum from bone marrow （BM） to tissue via monocytes as precursors. The development of new tools such as genetic lineage tracing,parabiosis and BM chimeras changed the paradigm of macrophage origin. In steady state, most resident macro-phages are of embryonic origin, whereas a monocyte origin remains prominent in pathological conditions. The findings of a proliferation of mature macrophages will oblige us to reappraise the relationship between proliferation and differentiation in macrophages. This review is based on the recent explosion of high impact articles on macrophage biology. It summarizes new data on the origin of macrophages and their self-renewal potential in steady states. While monocytes are required for intestinal macrophage development, the microglia is independent of monocyte influx and skin macrophages provide an excellent model of the balance between monocyte input and self-renewal. In addition, macrophage proliferation requires intrinsic and extrinsic factors including growth factors and cytokines. It also analyzes the impact of this new paradigm in human diseases such as athrosclerosis, cancer, infe-ctious diseases and neurodegenerative diseases. In atherosclerosis, the fnding of macrophage proliferation within the lesions will change our understanding of disease pathophysiology, this new paradigm may have therapeutical impact in the future.展开更多
Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis...Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis of IBS has impeded its treatment.Here,we report that the E3 ubiquitin ligase tripartite motif-containing 27(TRIM27)is weakly expressed in IBS but highly expressed in inflammatory bowel disease(IBD),a frequent chronic organic gastrointestinal disorder.Accordingly,knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms,including increased visceral hyperalgesia and abnormal stool features,as observed in IBS patients.Mechanistically,TRIM27 stabilizesβ-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell(ISC)self-renewal.Consistent with these findings,Trim27 deficiency disrupts organoid formation,which is rescued by reintroducing TRIM27 orβ-catenin.Furthermore,Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal.Taken together,these data indicate that TRIM27 is critical for maintaining gut homeostasis,suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS.Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.展开更多
Embryonic stem (ES) cells are characterized by their ability to indefinitely self-renew and potential to differentiate into all the cell lineages of the body. ES cells are considered to have potential applications in ...Embryonic stem (ES) cells are characterized by their ability to indefinitely self-renew and potential to differentiate into all the cell lineages of the body. ES cells are considered to have potential applications in regenerative medicine. In particular, the emergence of an ES cell analogue-induced pluripotent stem (iPS) cells via somatic cell reprogramming by co-expressing a limited number of critical stemness-related transcriptional factors has solved the problem of obtaining patient-specific pluripotent cells, encouraging researchers to develop more specific and functional cell lineages from ES or iPS cells for broad therapeutic applications. ES cell fate choice is delicately controlled by a core transcriptional network, epigenetic modification profiles and complex signaling cascades both intrinsically and extrinsically. Of these signals, transforming growth factor β (TGF-β) family members, including TGF-β, bone morphogenetic protein (BMP), Activin and Nodal, have been reported to influence cell self-renewal and a broad spectrum of lineage differentiation in ES cells, in accordance with the key roles of TGF-β family signaling in early embryo development. In this review, the roles of TGF-β family signals in coordinating ES cell fate determination are summarized.展开更多
Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs.They play key roles during development and their dysregulation gives rise to human diseases such as cancer.The recent de-...Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs.They play key roles during development and their dysregulation gives rise to human diseases such as cancer.The recent de-velopment of induced pluripotent stem cell(iPSC)technology which converts somatic cells to stem-like cells holds great promise for regenerative medicine.Nevertheless,the understanding of proliferation,dif-ferentiation,and self-renewal of stem cells and or-gan-specific progenitor cells is far from clear.Recently,the Hippo pathway was demonstrated to play important roles in these processes.The Hippo pathway is a newly established signaling pathway with critical functions in limiting organ size and suppressing tumorigenesis.This pathway was first found to inhibit cell proliferation and promote apoptosis,therefore regulating cell num-ber and organ size in both Drosophila and mammals.However,in several organs,disturbance of the pathway leads to specific expansion of the progenitor cell com-partment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and dif-ferentiation.In this review,we summarize current ob-servations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ de-velopment and tumorigenesis.展开更多
Objective： To investigate the effects and underlying molecular mechanisms of icariin （ICA） on self-renewal and differentiation of neural stem cells （NSCs）. Methods： NSCs were derived from forebrains of mice embr...Objective： To investigate the effects and underlying molecular mechanisms of icariin （ICA） on self-renewal and differentiation of neural stem cells （NSCs）. Methods： NSCs were derived from forebrains of mice embryos by mechanical dissociation into single cell suspension. The self-renewal of NSCs was measured by neurosphere formation assay. The proliferation of NSCs was detected by water-soluble tetrazolium （WST） and 5-ethynyl-2＇-deoxyuridine （EdU） incorporation assay. Protein expression of neuron-specific marker tubulin-βⅢ（TuJ1） and astrocyte-specific marker glial fibrillary acidic protein （GFAP） were measured by immunofluorescence and Western blotting. Using microarray, the differentially expressed genes （DEGs） were screened between NSCs with or without ICA treatment. The signaling pathways enriched by these DEGs and their role in mediating effects of ICA were analyzed. Results： ICA significantly promoted neurosphere formation of NSCs cultured in growth protocol in a dose-dependent manner and achieved the maximum effects at 100 nmol/L. ICA also increased optical absorbance value and EdU incorporation into nuclei of NSCs. ICA had no significant effects on the percentage of TuJ1 or GFAP-positive cells, and TuJ1 or GFAP protein expression in NSCs cultured in differentiation protocol. A total of 478 genes were found to be differentially regulated. Among signaling pathways significantly enriched by DEGs, mitogen activated protein kinase （MAPK） pathway was of interest. Blockade of extracellular signal-regulated kinase （ERK）/MAPK, other than p38/MAPK subfamily pathway partially abolished effects of ICA on neurosphere formation and EdU incorporation of NSCs. Conclusion： ICA can promote the self- renewal of NSCs at least partially through ERK/MAPK signaling pathway.展开更多
Spermatogonial stem cells （SSCs）, the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technolog...Spermatogonial stem cells （SSCs）, the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technology improvements, most importantly, transplantation assays and in vitro culture systems have greatly expanded our understanding of SSC self-renewal and differentiation. Many important molecules crucial for the balance between self-renewal and differentiation have been recently identified although the exact mechanism（s） remain largely undefined. In this review, we give a brief introduction to SSCs, and then focus on extrinsic and intrinsic factors controlling SSCs self-renewal and differentiation.展开更多
Liver cancer is highly heterogeneous,and the tumor tissue harbors a variety of cell types.Liver tumor initiating cells(TICs)well contribute to tumor heterogeneity and account for tumor initiation and metastasis,but th...Liver cancer is highly heterogeneous,and the tumor tissue harbors a variety of cell types.Liver tumor initiating cells(TICs)well contribute to tumor heterogeneity and account for tumor initiation and metastasis,but the molecular mechanisms of liver TIC self-renewal are elusive.Here,we identified a functional read-through rt-circRNA,termed rtcisE2F,that is highly expressed in liver cancer and liver TICs.rtcisE2F plays essential roles in the self-renewal and activities of liver TICs.rtcisE2F targets E2F6 and E2F3 mRNAs,attenuates mRNA turnover,and increases E2F6/E2F3 expression.Mechanistically,rtcisE2F functions as a scaffold of N^(6)-methyladenosine(m^(6)A)reader IGF2BP2 and E2F6/E2F3 mRNA.rtcisE2F promotes the association of E2F6/E2F3 mRNAs with IGF2BP2,and inhibits their association with another m^(6)A reader,YTHDF2.IGF2BP2 inhibits E2F6/E2F3 mRNA decay,whereas YTHDF2 promotes E2F6/E2F3 mRNA decay.By switching m^(6)A readers,rtcisE2F enhances E2F6/E2F3 mRNA stability.E2F6 and E2F3 are both required for liver TIC self-renewal and Wnt/β-catenin activation,and inhibition of these pathways is a potential strategy for preventing liver tumorigenesis and metastasis.In conclusion,the rtcisE2F-IGF2BP2/YTHDF2-E2F6/E2F3-Wnt/β-catenin axis drives liver TIC self-renewal and initiates liver tumorigenesis and metastasis,and may provide a strategy to eliminate liver TICs.展开更多
Long non-coding RNAs(lncRNAs)regulate transcription to control development and homeostasis in a variety of tissues and organs.However,their roles in the development of the cerebral cortex have not been well elucidated...Long non-coding RNAs(lncRNAs)regulate transcription to control development and homeostasis in a variety of tissues and organs.However,their roles in the development of the cerebral cortex have not been well elucidated.Here,a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral cortex.We further characterized a sense lncRNA,SenZfp536,which is transcribed downstream of and partially overlaps with the protein-coding gene Zfp536.Both SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing cortex.Zfp536 was cis-regulated by SenZfp536,which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes SenZfp536.Surprisingly,knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells(NPCs),respectively.Finally,overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 knockdown.The study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.展开更多
It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 su...It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain,we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs.Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone,the major regions for postnatal NSC activities.Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages.Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis.These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.展开更多
The self-renewal and pluripotency of embryonic stem cells (ESCs) is regulated by a network, which consists of a series of cell factors in microenviroments, a chain of transcription factors and certain signal conductio...The self-renewal and pluripotency of embryonic stem cells (ESCs) is regulated by a network, which consists of a series of cell factors in microenviroments, a chain of transcription factors and certain signal conduction pathways. This article reviews recent progress in this field to elucidate the mecha-nism involved.展开更多
Focusing on the business alliance scenario in blockchains,this paper proposes a new consensus mechanism named proof of rest(PoR)and strong smart contracts.The block structure and logic of PoR consensus are described.A...Focusing on the business alliance scenario in blockchains,this paper proposes a new consensus mechanism named proof of rest(PoR)and strong smart contracts.The block structure and logic of PoR consensus are described.And a consortium blockchain system supporting strong smart contracts is designed.We modify the difficulty value algorithm based on proof of work(PoW)and add adjustable parameters.The longer a node rests after creating a block,the less difficult it is to create another new block,hence the term PoR.The penalty for slack nodes,the joining and quitting of nodes,and the adjustment of the expected block creation time can all be accomplished using the strong smart contracts,so the consortium blockchain can realize self-renewal.展开更多
Mammalian spermatogenesis is a complicated and precisely controlled process that requires spermatogonial stem cells(SSCs).SSCs maintain the stem cell pool,balance self-renewal–commitment with differentiation,and prod...Mammalian spermatogenesis is a complicated and precisely controlled process that requires spermatogonial stem cells(SSCs).SSCs maintain the stem cell pool,balance self-renewal–commitment with differentiation,and produce millions of sperm daily.Self-renewal and differentiation are controlled by intrinsic factors within SSCs and extrinsic factors from the"niche."In this review,we discuss the biology of SSCs and the factors regulating their self-renewal and differentiation.展开更多
Human embryonic stem cells(hESCs)undergo self-renewal while maintaining pluripotency.However,the molecular mechanism that demonstrates how these cells maintain their undifferentiated state and how they self-renew is p...Human embryonic stem cells(hESCs)undergo self-renewal while maintaining pluripotency.However,the molecular mechanism that demonstrates how these cells maintain their undifferentiated state and how they self-renew is poorly understood.Here,we characterized an aneuploidy H1 hESC subline(named H1T)using karyotyping and comparative genomic hybridization(CGH)microarray.Because the H1T hESC line displays a self-renewal advantage while maintaining an undiffer-entiated state,we speculated that the expression patterns of specific genes which are related to pluripotency or differentiation were altered;therefore,we attempted to screen for molecules that are propitious for maintenance of stemness by performing a combination of mRNA and CGH microarray analysis which compared the aneuploidy H1T hESC subline versus the euploid H1 hESC line.It is discovered that some genes are up-regulated in H1T hESC subline such as TBX2 and Wnt3,while some are downregulated,for example,Fbxo7 and HMG2L1.Ourfindings should fascilitate the study of the complex signaling network which maintains hESC pluripotency and function.展开更多
基金supported by the Natural Science Foundation of Heilongjiang Province of China,Outstanding Youth Foundation,No.YQ2022H003 (to DW)。
文摘N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.
文摘In this Editorial review,we would like to focus on a very recent discovery showing the global autosomal gene regulation by Y-and inactivated X-chromosomal transcription factors,zinc finger gene on the Y chromosome(ZFY)and zinc finger protein X-linked(ZFX).ZFX and ZFY are both zinc-finger proteins that encode general transcription factors abundant in hematopoietic and embryonic stem cells.Although both proteins are homologs,interestingly,the regulation of self-renewal by these transcriptional factors is almost exclusive to ZFX.This fact implies that there are some differential roles between ZFX and ZFY in regulating the maintenance of self-renewal activity in stem cells.Besides the maintenance of stemness,ZFX overexpression or mutations may be linked to certain cancers.Although cancers and stem cells are double-edged swords,there is no study showing the link between ZFX activity and the telomere.Thus,stemness or cancers with ZFX may be linked to other molecules,such as Oct4,Sox2,Klf4,and others.Based on very recent studies and a few lines of evidence in the past decade,it appears that the ZFX is linked to the canonical Wnt signaling,which is one possible mechanism to explain the role of ZFX in the self-renewal of stem cells.
文摘AIM： To identify cancer stern cells （CSCs） in human gallbladder carcinomas （GBCs）. METHODS： Primary GBC cells were cultured under serum-free conditions to produce floating spheres. The stem-cell properties of the sphere-forming cells, including self-renewal, differentiation potential, chemoresistance and tumorigenicity, were determined in vitro or in vivo. Cell surface expression of CD133 was investigated in primary tumors and in spheroid cells using flow cytometry. The sphere-colony-formation ability and tumorigenicity of CD133＋ cells were assayed.floating spheroids were generated from primary GBC cells, and these sphere-forming cells could generate new progeny spheroids in serum-free media. Spheroid cells were differentiated under serum-containing conditions with downregulation of the stem cell markers Oct-4, Nanog, and nestin （P 〈 0.05）. The differentiated cells showed lower spheroid-colony-formation ability than the original spheroid cells （P 〈 0.05）. Spheroid ceils were more resistant to chemotherapeutic reagents than the congenetic adherent cells （P 〈 0.05）. Flow cytometry showed enriched CD133＋ population in sphereforming cells （P 〈 0.05）. CD133＋ cells possessed high colony-formation ability than the CD133 population （P 〈 0.01）. CD133＋ cells injected into nude mice revealed higher tumorigenicity than their antigen-negative counterparts （P 〈 0.05）. CONCLUSION： CD133 may be a cell surface marker for CSCs in GBC.
文摘AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （20, 40, 80, 160, 200 ng/mL） in serum-free medium for 24 h. Cell proliferation was measured by Brdu incorporation analysis; untreated WB-F344 cells were taken as controls. After treatment with Wnt3a （160 ng/mL） for 24 h, subcellular localization and protein expression of p-catenin in WB-F344 cells treated and untreated with Wnt3a were examined by immunofluorescence staining and Western blot analysis. CyclinD1 mRNA expression was determined by semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR）. The mRNA levels of some phenotypic markers （AFP, CK-19, ALB） and two hepatic nuclear factors （HNF-4, HIVF-6） were measured by RT-PCR. Expressions of CK-19 and AFP protein were detected by Western blot analysis. RESULTS： Wnt3a promoted proliferation of WB-F344 cells. Stimulation of WB-F344 cells with recombinant Wnt3a resulte^l in accumulation of the transcriptional activator β-catenin, together with its translocation into the nuclei, and up-regulated typical Wnt target gene CyclinD1. After 3 d of Wnt3a treatment in the absence of serum, WB-F344 cells retained their bipotential to express several specific phenotypic markers of hepatocytes and cholangiocytes, such as AFP and CK-19, following activation of the canonical Wnt signaling pathway. CONCLUSION： The canonical Wnt signaling pathway promotes proliferation and self-renewal of rat hepatic oval cells.
文摘A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigenetic processes such as DNA methylation and chromatin remodeling. Several cytokines/growth factors have been identified as critical ES cell regulators. However, there is a gap in our knowledge of the intracellular signaling pathways linking extracellular signals to transcriptional regulation in ES cells. This short review discusses the physiological role of Shp2, a cytoplasmic tyro- sine phosphatase, in the molecular switch governing ES cell self-renewal versus differentiation. Shp2 promotes ES cell differentiation, mainly through bi-directional modulation of Erk and Stat3 pathways. Deletion of Shp2 in mouse ES cells results in more efficient self-renewal. This observation provides the impetus to develop Shp2 inhibitors for maintenance and amplification of ES cells in culture.
文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
基金Supported by Capital’s Funds for Health Improvement and Research (CFH),No. 2020-2-2175Beijing Talents Project
文摘Cancer stem cells(CSCs)possess self-renewal and differentiation potential,which may be related to recurrence,metastasis,and radiochemotherapy resistance during tumor treatment.Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span.Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics.This review summarizes the relationship between CSCs and amino acid metabolism,and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal,survival and stemness.The ultimate goal is to identify new targets and research directions for elimination of CSCs.
文摘The origin of macrophages has been considered since several decades to be a continuum from bone marrow （BM） to tissue via monocytes as precursors. The development of new tools such as genetic lineage tracing,parabiosis and BM chimeras changed the paradigm of macrophage origin. In steady state, most resident macro-phages are of embryonic origin, whereas a monocyte origin remains prominent in pathological conditions. The findings of a proliferation of mature macrophages will oblige us to reappraise the relationship between proliferation and differentiation in macrophages. This review is based on the recent explosion of high impact articles on macrophage biology. It summarizes new data on the origin of macrophages and their self-renewal potential in steady states. While monocytes are required for intestinal macrophage development, the microglia is independent of monocyte influx and skin macrophages provide an excellent model of the balance between monocyte input and self-renewal. In addition, macrophage proliferation requires intrinsic and extrinsic factors including growth factors and cytokines. It also analyzes the impact of this new paradigm in human diseases such as athrosclerosis, cancer, infe-ctious diseases and neurodegenerative diseases. In atherosclerosis, the fnding of macrophage proliferation within the lesions will change our understanding of disease pathophysiology, this new paradigm may have therapeutical impact in the future.
基金supported by the National Key Research and Development Project of China(2021YFA1300200 to CHL and LZ,2022YFC2302900 to CHL and JW)the National Natural Science Foundation of China(81825014 to CHL,31830003 to CHL,82022041 to JW and 81871616 to JW)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29020000 to CHL)Youth Innovation Promotion Association CAS(2018118 to JW)the State Key Laboratory of Proteomics(SKLP-K202001 to LZ and SKLPO202003 to JW).
文摘Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis of IBS has impeded its treatment.Here,we report that the E3 ubiquitin ligase tripartite motif-containing 27(TRIM27)is weakly expressed in IBS but highly expressed in inflammatory bowel disease(IBD),a frequent chronic organic gastrointestinal disorder.Accordingly,knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms,including increased visceral hyperalgesia and abnormal stool features,as observed in IBS patients.Mechanistically,TRIM27 stabilizesβ-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell(ISC)self-renewal.Consistent with these findings,Trim27 deficiency disrupts organoid formation,which is rescued by reintroducing TRIM27 orβ-catenin.Furthermore,Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal.Taken together,these data indicate that TRIM27 is critical for maintaining gut homeostasis,suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS.Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
基金supported by grants from the National Natural Science Foundation of China (Grant Nos. 30921004 and 30930050)the National Basic Research Program of China (Grant Nos of China 2006CB943401, 2006CB910102 and 2010CB 833706)
文摘Embryonic stem (ES) cells are characterized by their ability to indefinitely self-renew and potential to differentiate into all the cell lineages of the body. ES cells are considered to have potential applications in regenerative medicine. In particular, the emergence of an ES cell analogue-induced pluripotent stem (iPS) cells via somatic cell reprogramming by co-expressing a limited number of critical stemness-related transcriptional factors has solved the problem of obtaining patient-specific pluripotent cells, encouraging researchers to develop more specific and functional cell lineages from ES or iPS cells for broad therapeutic applications. ES cell fate choice is delicately controlled by a core transcriptional network, epigenetic modification profiles and complex signaling cascades both intrinsically and extrinsically. Of these signals, transforming growth factor β (TGF-β) family members, including TGF-β, bone morphogenetic protein (BMP), Activin and Nodal, have been reported to influence cell self-renewal and a broad spectrum of lineage differentiation in ES cells, in accordance with the key roles of TGF-β family signaling in early embryo development. In this review, the roles of TGF-β family signals in coordinating ES cell fate determination are summarized.
基金This work was supported by grants from the Na-tional Natural Science Foundation of China
文摘Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs.They play key roles during development and their dysregulation gives rise to human diseases such as cancer.The recent de-velopment of induced pluripotent stem cell(iPSC)technology which converts somatic cells to stem-like cells holds great promise for regenerative medicine.Nevertheless,the understanding of proliferation,dif-ferentiation,and self-renewal of stem cells and or-gan-specific progenitor cells is far from clear.Recently,the Hippo pathway was demonstrated to play important roles in these processes.The Hippo pathway is a newly established signaling pathway with critical functions in limiting organ size and suppressing tumorigenesis.This pathway was first found to inhibit cell proliferation and promote apoptosis,therefore regulating cell num-ber and organ size in both Drosophila and mammals.However,in several organs,disturbance of the pathway leads to specific expansion of the progenitor cell com-partment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and dif-ferentiation.In this review,we summarize current ob-servations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ de-velopment and tumorigenesis.
基金Supported by the National Basic Research Program in China(No.2007CB507400)partially by the Project of National Natural Science Foundation of China(No.30873319 and 30901888)
文摘Objective： To investigate the effects and underlying molecular mechanisms of icariin （ICA） on self-renewal and differentiation of neural stem cells （NSCs）. Methods： NSCs were derived from forebrains of mice embryos by mechanical dissociation into single cell suspension. The self-renewal of NSCs was measured by neurosphere formation assay. The proliferation of NSCs was detected by water-soluble tetrazolium （WST） and 5-ethynyl-2＇-deoxyuridine （EdU） incorporation assay. Protein expression of neuron-specific marker tubulin-βⅢ（TuJ1） and astrocyte-specific marker glial fibrillary acidic protein （GFAP） were measured by immunofluorescence and Western blotting. Using microarray, the differentially expressed genes （DEGs） were screened between NSCs with or without ICA treatment. The signaling pathways enriched by these DEGs and their role in mediating effects of ICA were analyzed. Results： ICA significantly promoted neurosphere formation of NSCs cultured in growth protocol in a dose-dependent manner and achieved the maximum effects at 100 nmol/L. ICA also increased optical absorbance value and EdU incorporation into nuclei of NSCs. ICA had no significant effects on the percentage of TuJ1 or GFAP-positive cells, and TuJ1 or GFAP protein expression in NSCs cultured in differentiation protocol. A total of 478 genes were found to be differentially regulated. Among signaling pathways significantly enriched by DEGs, mitogen activated protein kinase （MAPK） pathway was of interest. Blockade of extracellular signal-regulated kinase （ERK）/MAPK, other than p38/MAPK subfamily pathway partially abolished effects of ICA on neurosphere formation and EdU incorporation of NSCs. Conclusion： ICA can promote the self- renewal of NSCs at least partially through ERK/MAPK signaling pathway.
基金ACKNOWLEDGM ENTS This work was supported by National Basic Research Program of China （grant numbers 2013CB967401 http：//www.most.gov.cn） and the National Nature Science Foundation of China （grant numbers 81370675, 81200472 and 81421061+1 种基金 http：//www.nsfc.gov.cn）, and Shanghai Jiao Tong University Medicine-Engineering Fund （grant numberYG2013ZD04 http：//www.sjtu. edu.cn）.
文摘Spermatogonial stem cells （SSCs）, the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technology improvements, most importantly, transplantation assays and in vitro culture systems have greatly expanded our understanding of SSC self-renewal and differentiation. Many important molecules crucial for the balance between self-renewal and differentiation have been recently identified although the exact mechanism（s） remain largely undefined. In this review, we give a brief introduction to SSCs, and then focus on extrinsic and intrinsic factors controlling SSCs self-renewal and differentiation.
基金This work was supported by the National Natural Science Foundation of China(31922024,81872411,32170874,82173176)Science Foundation for Excellent Young Scholars in Henan(202300410358).
文摘Liver cancer is highly heterogeneous,and the tumor tissue harbors a variety of cell types.Liver tumor initiating cells(TICs)well contribute to tumor heterogeneity and account for tumor initiation and metastasis,but the molecular mechanisms of liver TIC self-renewal are elusive.Here,we identified a functional read-through rt-circRNA,termed rtcisE2F,that is highly expressed in liver cancer and liver TICs.rtcisE2F plays essential roles in the self-renewal and activities of liver TICs.rtcisE2F targets E2F6 and E2F3 mRNAs,attenuates mRNA turnover,and increases E2F6/E2F3 expression.Mechanistically,rtcisE2F functions as a scaffold of N^(6)-methyladenosine(m^(6)A)reader IGF2BP2 and E2F6/E2F3 mRNA.rtcisE2F promotes the association of E2F6/E2F3 mRNAs with IGF2BP2,and inhibits their association with another m^(6)A reader,YTHDF2.IGF2BP2 inhibits E2F6/E2F3 mRNA decay,whereas YTHDF2 promotes E2F6/E2F3 mRNA decay.By switching m^(6)A readers,rtcisE2F enhances E2F6/E2F3 mRNA stability.E2F6 and E2F3 are both required for liver TIC self-renewal and Wnt/β-catenin activation,and inhibition of these pathways is a potential strategy for preventing liver tumorigenesis and metastasis.In conclusion,the rtcisE2F-IGF2BP2/YTHDF2-E2F6/E2F3-Wnt/β-catenin axis drives liver TIC self-renewal and initiates liver tumorigenesis and metastasis,and may provide a strategy to eliminate liver TICs.
基金This work was supported by grants from the National Key R&D Program of China(2018YFA0800700)the National Natural Science Foundation of China(31970770,31970676,and 31671418)+2 种基金the Natural Science Foundation of Hubei Province,China(2018CFA016)Fundamental Research Funds for the Central Universities,the Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University(TFJC2018005)State Key Laboratory Special Fund 2060204.
文摘Long non-coding RNAs(lncRNAs)regulate transcription to control development and homeostasis in a variety of tissues and organs.However,their roles in the development of the cerebral cortex have not been well elucidated.Here,a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral cortex.We further characterized a sense lncRNA,SenZfp536,which is transcribed downstream of and partially overlaps with the protein-coding gene Zfp536.Both SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing cortex.Zfp536 was cis-regulated by SenZfp536,which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes SenZfp536.Surprisingly,knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells(NPCs),respectively.Finally,overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 knockdown.The study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.
文摘It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain,we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs.Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone,the major regions for postnatal NSC activities.Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages.Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis.These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.
基金Supported by the State 863 High Technology R&D Project of China (Grant No. 2006AA02A107)the National Key Project for Basic Research of China (Grant No. 2005CB522702 to X. T. Pei)
文摘The self-renewal and pluripotency of embryonic stem cells (ESCs) is regulated by a network, which consists of a series of cell factors in microenviroments, a chain of transcription factors and certain signal conduction pathways. This article reviews recent progress in this field to elucidate the mecha-nism involved.
基金supported by the National Key R&D Program of China(No.2018YFB2101100).
文摘Focusing on the business alliance scenario in blockchains,this paper proposes a new consensus mechanism named proof of rest(PoR)and strong smart contracts.The block structure and logic of PoR consensus are described.And a consortium blockchain system supporting strong smart contracts is designed.We modify the difficulty value algorithm based on proof of work(PoW)and add adjustable parameters.The longer a node rests after creating a block,the less difficult it is to create another new block,hence the term PoR.The penalty for slack nodes,the joining and quitting of nodes,and the adjustment of the expected block creation time can all be accomplished using the strong smart contracts,so the consortium blockchain can realize self-renewal.
文摘Mammalian spermatogenesis is a complicated and precisely controlled process that requires spermatogonial stem cells(SSCs).SSCs maintain the stem cell pool,balance self-renewal–commitment with differentiation,and produce millions of sperm daily.Self-renewal and differentiation are controlled by intrinsic factors within SSCs and extrinsic factors from the"niche."In this review,we discuss the biology of SSCs and the factors regulating their self-renewal and differentiation.
基金supported by a grant from the NIH PO1 Ca70970.This research was partially supported by grants from the National Natural Science Foundation of China(Grant No.31025016).
文摘Human embryonic stem cells(hESCs)undergo self-renewal while maintaining pluripotency.However,the molecular mechanism that demonstrates how these cells maintain their undifferentiated state and how they self-renew is poorly understood.Here,we characterized an aneuploidy H1 hESC subline(named H1T)using karyotyping and comparative genomic hybridization(CGH)microarray.Because the H1T hESC line displays a self-renewal advantage while maintaining an undiffer-entiated state,we speculated that the expression patterns of specific genes which are related to pluripotency or differentiation were altered;therefore,we attempted to screen for molecules that are propitious for maintenance of stemness by performing a combination of mRNA and CGH microarray analysis which compared the aneuploidy H1T hESC subline versus the euploid H1 hESC line.It is discovered that some genes are up-regulated in H1T hESC subline such as TBX2 and Wnt3,while some are downregulated,for example,Fbxo7 and HMG2L1.Ourfindings should fascilitate the study of the complex signaling network which maintains hESC pluripotency and function.
