In the mammalian central nervous system,nerve-glia antigen 2(NG2)glia are considered the fourth glial population in addition to astrocytes,oligodendrocytes and microglia.The fate of NG2 glia in vivo has been carefully...In the mammalian central nervous system,nerve-glia antigen 2(NG2)glia are considered the fourth glial population in addition to astrocytes,oligodendrocytes and microglia.The fate of NG2 glia in vivo has been carefully studied in several transgenic mouse models using the Cre/loxP strategy.There is a clear agreement that NG2 glia mainly serve as progenitors for oligodendrocytes and a subpopulation of astrocytes mainly in the ventral forebrain,whereas the existence of a neurogenic potential of NG2 glia is lack of adequate evidence.This mini review summarizes the findings from recent studies regarding the fate of NG2 glia during development.We will highlight the age-and-region-dependent heterogeneity of the NG2 glia differentiation potential.We will also discuss putative reasons for inconsistent findings in various transgenic mouse lines of previous studies.展开更多
Cell fate determination is a basic developmental process during the growth of multicellular organisms.Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells...Cell fate determination is a basic developmental process during the growth of multicellular organisms.Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells of the aerial tissues and roots respectively, and they serve as excellent models for understanding the molecular mechanisms controlling cell fate determination and cell morphogenesis. The regulation of trichome and root hair formationis a complex program that consists of the integration of hormonal signals with a large number of transcriptional factors, including MYB and b HLH transcriptional factors.Studies during recent years have uncovered an important role of C2H2 type zinc finger proteins in the regulation of epidermal cell fate determination. Here in this minireview we briefly summarize the involvement of C2H2 zinc finger proteins in the control of trichome and root hair formation in Arabidopsis.展开更多
Neural stem cells(NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, h...Neural stem cells(NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with animportant role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.展开更多
5-Bromo-2′-deoxyuridine(BrdU)is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle.BrdU is widely used in fate-mapping studies of embryonic and adult neu...5-Bromo-2′-deoxyuridine(BrdU)is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle.BrdU is widely used in fate-mapping studies of embryonic and adult neurogenesis to identify newborn neurons,however side effects on neural stem cells and their progeny have been reported.In vivo astrocyte-to-neuron(AtN)conversion is a new approach for generating newborn neurons by directly converting endogenous astrocytes into neurons.The BrdU-labeling strategy has been used to trace astrocyte-converted neurons,but whether BrdU has any effect on the AtN conversion is unknown.Here,while conducting a NeuroD1-mediated AtN conversion study using BrdU to label dividing reactive astrocytes following ischemic injury,we accidentally discovered that BrdU inhibited AtN conversion.We initially found a gradual reduction in BrdU-labeled astrocytes during NeuroD1-mediated AtN conversion in the mouse cortex.Although most NeuroD1-infected astrocytes were converted into neurons,the number of BrdU-labeled neurons was surprisingly low.To exclude the possibility that this BrdU inhibition was caused by the ischemic injury,we conducted an in vitro AtN conversion study by overexpressing NeuroD1 in cultured cortical astrocytes in the presence or absence of BrdU.Surprisingly,we also found a significantly lower conversion rate and a smaller number of converted neurons in the BrdU-treated group compared with the untreated group.These results revealed an unexpected inhibitory effect of BrdU on AtN conversion,suggesting more caution is needed when using BrdU in AtN conversion studies and in data interpretation.展开更多
Mesenchymal stem cells(MSCs)are multipotent cells that can differentiate into various mesodermal lines forming fat,muscle,bone,and other lineages of connective tissue.MSCs possess plasticity and under special metaboli...Mesenchymal stem cells(MSCs)are multipotent cells that can differentiate into various mesodermal lines forming fat,muscle,bone,and other lineages of connective tissue.MSCs possess plasticity and under special metabolic conditions may transform into cells of unusual phenotypes originating from ecto-and endoderm.After transplantation,MSCs release the humoral factors promoting regeneration of the damaged tissue.During last five years,the numbers of registered clinical trials of MSCs have increased about 10 folds.This gives evidence that MSCs present a new promising resource for cell therapy of the most dangerous diseases.The efficacy of the MSCs therapy is limited by low possibilities to regulate their conversion into cells of damaged tissues that is implemented by the pRb-E2F signaling.The widely accepted viewpoint addresses pRb as ubiquitous regulator of cell cycle and tumor suppressor.However,current publications suggest that basic function of the pRb-E2F signaling in development is to regulate cell fate and differentiation.Through facultative and constitutive chromatin modifications,pRb-E2F signaling promotes transient and stable cells quiescence,cell fate choice to differentiate,to senesce,or to die.Loss of pRb is associated with cancer cell fate.pRb regulates cell fate by retaining quiescence of one cell population in favor of commitment of another or by suppression of genes of different cell phenotype.pRb is the founder member of the“pocket protein”family possessing functional redundancy.Critical increase in the efficacy of the MSCs based cell therapy will depend on precise understanding of various aspects of the pRb-E2F signaling.展开更多
Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. How...Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. However, the underlying mechanisms of IP3R- regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells （mESCs）. Deletion of IP3Rs （IP3R-tKO） reduced FIkl＋/PDGFRα- hematopoietic mesoderm, c-Kit＋/CD41＋ hematopoietic progenitor ceil population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Ely2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2＋ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Ely2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2＋-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2＋-calcineurin-NFATc3- Etv2 pathway.展开更多
Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastroi...Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.展开更多
Polydendrocytes （NG2 cells） are a distinct type of glia that populate the developing and adult central nervous systems （CNS）. In the adult CNS, they retain mitotic activity and represent the largest proliferating ...Polydendrocytes （NG2 cells） are a distinct type of glia that populate the developing and adult central nervous systems （CNS）. In the adult CNS, they retain mitotic activity and represent the largest proliferating cell popula- tion. Genetic and epigenetic mechanisms regulate the fate of polydendrocytes, which give rise to both oligo- dendrocytes and astrocytes. In addition, polydendrocytes actively differentiate into myelin-forming oligodendro- cytes in response to demyelination. This review summarizes the current knowledge regarding polydendrocyte development, which provides an important basis for understanding the mechanisms that lead to the remyelina- tion of demyelinated lesions.展开更多
Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty a...Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.展开更多
基金This work was supported by grants from the Deutsche Forschungsgemeinschaft DFG Sino-German joint project(Kl 503/14-1)to WH,DFG FOR 2289 to ASfrom the Saarland University Medical Faculty HOMFOR2015 and HOMFORexzellenz2016 to AS and WH,respectivelyWH was also supported by DFG SFB 894 and the European Commission EC-H2020 FET ProAct Neurofibres.
文摘In the mammalian central nervous system,nerve-glia antigen 2(NG2)glia are considered the fourth glial population in addition to astrocytes,oligodendrocytes and microglia.The fate of NG2 glia in vivo has been carefully studied in several transgenic mouse models using the Cre/loxP strategy.There is a clear agreement that NG2 glia mainly serve as progenitors for oligodendrocytes and a subpopulation of astrocytes mainly in the ventral forebrain,whereas the existence of a neurogenic potential of NG2 glia is lack of adequate evidence.This mini review summarizes the findings from recent studies regarding the fate of NG2 glia during development.We will highlight the age-and-region-dependent heterogeneity of the NG2 glia differentiation potential.We will also discuss putative reasons for inconsistent findings in various transgenic mouse lines of previous studies.
基金supported by National Natural Science Foundation of China (Grant Nos. 31370215, 31228002 and 31970167)International Scientific and Technological Cooperation Project of Science and Technology Department of Zhejiang Province (Grant No. 2013C24007)+1 种基金Zhejiang Provincial Natural Science Foundation of China (Grant No. Z3110004)Ph.D.Programs Foundation of Ministry of Education of China (Grant No. 20120101110079)
文摘Cell fate determination is a basic developmental process during the growth of multicellular organisms.Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells of the aerial tissues and roots respectively, and they serve as excellent models for understanding the molecular mechanisms controlling cell fate determination and cell morphogenesis. The regulation of trichome and root hair formationis a complex program that consists of the integration of hormonal signals with a large number of transcriptional factors, including MYB and b HLH transcriptional factors.Studies during recent years have uncovered an important role of C2H2 type zinc finger proteins in the regulation of epidermal cell fate determination. Here in this minireview we briefly summarize the involvement of C2H2 zinc finger proteins in the control of trichome and root hair formation in Arabidopsis.
文摘Neural stem cells(NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with animportant role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.
基金supported by the Natural Science Foundation of Guangdong Province of China,Nos.2021A1515011237(to WL),2020A1515010854(to QSW)the National Natural Science Foundation of China,Nos.U1801681(to GC),31701291(to WL)the Guangdong Province Science and Technology Planning Project of China,No.2018B030332001(to GC)。
文摘5-Bromo-2′-deoxyuridine(BrdU)is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle.BrdU is widely used in fate-mapping studies of embryonic and adult neurogenesis to identify newborn neurons,however side effects on neural stem cells and their progeny have been reported.In vivo astrocyte-to-neuron(AtN)conversion is a new approach for generating newborn neurons by directly converting endogenous astrocytes into neurons.The BrdU-labeling strategy has been used to trace astrocyte-converted neurons,but whether BrdU has any effect on the AtN conversion is unknown.Here,while conducting a NeuroD1-mediated AtN conversion study using BrdU to label dividing reactive astrocytes following ischemic injury,we accidentally discovered that BrdU inhibited AtN conversion.We initially found a gradual reduction in BrdU-labeled astrocytes during NeuroD1-mediated AtN conversion in the mouse cortex.Although most NeuroD1-infected astrocytes were converted into neurons,the number of BrdU-labeled neurons was surprisingly low.To exclude the possibility that this BrdU inhibition was caused by the ischemic injury,we conducted an in vitro AtN conversion study by overexpressing NeuroD1 in cultured cortical astrocytes in the presence or absence of BrdU.Surprisingly,we also found a significantly lower conversion rate and a smaller number of converted neurons in the BrdU-treated group compared with the untreated group.These results revealed an unexpected inhibitory effect of BrdU on AtN conversion,suggesting more caution is needed when using BrdU in AtN conversion studies and in data interpretation.
基金supported by the Russian Foundation for Basic Research(projects Nos.12-04-00252 and 14-04-31115).
文摘Mesenchymal stem cells(MSCs)are multipotent cells that can differentiate into various mesodermal lines forming fat,muscle,bone,and other lineages of connective tissue.MSCs possess plasticity and under special metabolic conditions may transform into cells of unusual phenotypes originating from ecto-and endoderm.After transplantation,MSCs release the humoral factors promoting regeneration of the damaged tissue.During last five years,the numbers of registered clinical trials of MSCs have increased about 10 folds.This gives evidence that MSCs present a new promising resource for cell therapy of the most dangerous diseases.The efficacy of the MSCs therapy is limited by low possibilities to regulate their conversion into cells of damaged tissues that is implemented by the pRb-E2F signaling.The widely accepted viewpoint addresses pRb as ubiquitous regulator of cell cycle and tumor suppressor.However,current publications suggest that basic function of the pRb-E2F signaling in development is to regulate cell fate and differentiation.Through facultative and constitutive chromatin modifications,pRb-E2F signaling promotes transient and stable cells quiescence,cell fate choice to differentiate,to senesce,or to die.Loss of pRb is associated with cancer cell fate.pRb regulates cell fate by retaining quiescence of one cell population in favor of commitment of another or by suppression of genes of different cell phenotype.pRb is the founder member of the“pocket protein”family possessing functional redundancy.Critical increase in the efficacy of the MSCs based cell therapy will depend on precise understanding of various aspects of the pRb-E2F signaling.
基金This study was supported by grants from the National Natural Science Foundation of China （31030050, 81520108004, and 81470422 to H.-T.Y.）, the Strategic Priority Research Program of Chinese Academy of Sciences （XDA01020204 to H.-T.Y.）, the National Basic Research Program of China （2014CB965100 to H.-T.Y.）, the National Science and Technology Major Project （2012ZX09501001 to H.-T.Y.）, and the Shenzhen Science, Technology and Innovation Committee OCYI 20160428154108239 to K.O.）.
文摘Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. However, the underlying mechanisms of IP3R- regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells （mESCs）. Deletion of IP3Rs （IP3R-tKO） reduced FIkl＋/PDGFRα- hematopoietic mesoderm, c-Kit＋/CD41＋ hematopoietic progenitor ceil population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Ely2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2＋ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Ely2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2＋-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2＋-calcineurin-NFATc3- Etv2 pathway.
基金supported by the National Natural Science Foundation of China(Nos.82030107,81973247,81872815,81872826,and 81690263)Science and Technology Commission of Shanghai Municipality(Nos.19XD1400300,19430741400,and 19410761200,China)。
文摘Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.
基金supported by grants from the US National Institutes of Healththe National Multiple Sclerosis Societythe Connecticut Stem Cell Research Program
文摘Polydendrocytes （NG2 cells） are a distinct type of glia that populate the developing and adult central nervous systems （CNS）. In the adult CNS, they retain mitotic activity and represent the largest proliferating cell popula- tion. Genetic and epigenetic mechanisms regulate the fate of polydendrocytes, which give rise to both oligo- dendrocytes and astrocytes. In addition, polydendrocytes actively differentiate into myelin-forming oligodendro- cytes in response to demyelination. This review summarizes the current knowledge regarding polydendrocyte development, which provides an important basis for understanding the mechanisms that lead to the remyelina- tion of demyelinated lesions.
基金supported by the National Natural Science Foundation of China(Nos.82030107,81973247,81872815,81872826,and 81690263)Science and Technology Commission of Shanghai Municipality(Nos.19XD1400300,19430741400,and 19410761200,China).
文摘Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.
