Adult stem/progenitor cells play important roles in tissue homeostasis and have important implications for regenerativemedicine.It was once thought that formation of new blood vessels in adult only occurs through angi...Adult stem/progenitor cells play important roles in tissue homeostasis and have important implications for regenerativemedicine.It was once thought that formation of new blood vessels in adult only occurs through angiogenesis,a processwhereby new vessels are formed from existing mature endothelial cells;while vasculogenesis,where new vessels arederived from differentiation of endothelial progenitor cells(EPCs),was thought to occur exclusively in embryos.Thediscovery of adult EPCs a few years ago has changed this old paradigm;and subsequent studies showed that EPCs maybe a promising tool for the treatment of vascular disorders.However,there have been conflicting reports on subtypes,surface markers,and functions of EPCs;and thus the exact origin and identity of EPCs remain to be defined.A commonapproach to obtain EPCs is to isolate and culture mononuclear cells from peripheral blood and to select adherent cells展开更多
Prostate cancer is one of the leading health threats to man,and like many other cancers,early detection and treatment iscrucial to improving the prognosis of patients.Progression of the disease from noninvasive high-g...Prostate cancer is one of the leading health threats to man,and like many other cancers,early detection and treatment iscrucial to improving the prognosis of patients.Progression of the disease from noninvasive high-grade prostatic intraepi-thelial neoplasia (HGPIN) to invasive adenocarcinoma is linked to the action of a group of proteolytic enzymes calledmatrix metalloproteinases (MMPs),which digest various components of the extracellular matrix and thus open waysfor tumor metastasis.Previous studies have shown that one MMP,MMP-26,is expressed at a significantly higher levelin human prostate carcinoma than in normal prostate tissues,and that it appears to play an important role in promotinginvasion of prostate cancer cells [1].In this issue of Cell Research,Lee et al.report detailed analyses of the expressionpattern of MMP-26,along with its most potent endogenous inhibitor,TIMP-4 (TIMP stands for tissue inhibitor ofmetal-loproteinases),in a number of prostate cancer samples derived from human patients [2].Interestingly,they found展开更多
Ovarian cancer is one of the most lethal malignancies in women.Identification of new therapeutic targets would provideopportunities for developing potentially more effective treatment regimes.In the July issue of Cell...Ovarian cancer is one of the most lethal malignancies in women.Identification of new therapeutic targets would provideopportunities for developing potentially more effective treatment regimes.In the July issue of Cell Research,Cao et al.reports that glycogen synthase kinase-3β(GSK-3β)plays an important role in positively regulating the proliferation ofhuman ovarian cancer cells,and thus it may represent such a target[1].GSK-3β is a serine/threonine kinase that is knownto be involved in regulation ofβ-catenin signaling,where it participates in the formation of a multi-component destructioncomplex that promotes the phosphorylation and subsequent degradation of β-catenin.Given that overactive β-cateninsignaling is involved in many forms of human cancer,this classic mode of GSK-3β action should qualify it as a'tumorsuppressor'.Intriguingly,however,two recent studies have implicated that GSK-3β may actually play a pro-tumor rolein pancreatic and colorectal cancers[2,3].Since ovarian tumors often exhibit increased expression of GSK-3β,theserecent findings prompted Cao et al.to examine the potential role of GSK-3β in ovarian cancer cells.展开更多
PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a...PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.展开更多
Proteasome-mediated degradation and autophagy are the two major pathways mediating the turnover of cellularproteins.The proteasomal pathway is known to be a highly specific and regulated process mediating the degradat...Proteasome-mediated degradation and autophagy are the two major pathways mediating the turnover of cellularproteins.The proteasomal pathway is known to be a highly specific and regulated process mediating the degradationof short-lived proteins such as many important factors involved in cellular signaling.In contrast,it is generally thoughtthat autophagy is rather nonselective as it is responsible for the bulk degradation of long-lived proteins and organelles.Challenging this general view,in this issue of Cell Research,Qing et al.report that selective degradation of the IκBkinase(IKK)triggered by the loss of Hsp90 function is mediated by autophagy[1].展开更多
JMJD3(KDM6B)is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression.However,the function of JMJD3 in vivo is not well understood.Here we show that JMJD3 is highly expressed in cells of th...JMJD3(KDM6B)is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression.However,the function of JMJD3 in vivo is not well understood.Here we show that JMJD3 is highly expressed in cells of the chondrocyte lineage,especially in prehypertrophic and hypertrophic chondrocytes,during endochondral ossification.Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes,and thereby marked retardation of endochondral ossification in mice.Genetically,JMJD3 associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes.Biochemically,JMJD3 associates with and enhances RUNX2 activity by derepression of Runx2 and Ihh transcription throughits H3K27me3 demethylase activity.These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation.展开更多
In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly...In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly understood.Here,we studied the infection and pathogenesis of a new 2009 pandemic strain,A/Wenshan/01/2009 H1N1,in China in human airway epithelial cell lines compared with contemporary seasonal H1N1 influenza virus.Our results showed that viral infection by the A/Wenshan H1N1 induced significant apoptotic cell death in both the human nasopharyngeal carcinoma cell line CNE-2Z and the human lung adenocarcinoma cell line A549.The A/Wenshan H1N1 virus enters both of these cell types more efficiently than the seasonal influenza virus.Viral entry in both cell lines was shown to be mediated by clathrin-and dynamin-dependent endocytosis.Therefore,we discovered that the 2009 pandemic H1N1 strain,A/Wenshan/01/2009,can induce apoptotic cell death in epithelial cells of the human respiratory tract,suggesting a molecular pathogenesis for the 2009 pandemic H1N1.展开更多
Group 2 innate lymphoid cells(ILC2s)are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13,which mediate the type 2 immune response.However,specific drug targets on lung ILC2s have rarely been...Group 2 innate lymphoid cells(ILC2s)are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13,which mediate the type 2 immune response.However,specific drug targets on lung ILC2s have rarely been reported.Previous studies have shown that type 2 cytokines,such as IL-5 and IL-13,are related to depression.Here,we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression.Interestingly,serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation.Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs.Furthermore,an HTR2A selective agonist(DOI)impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro.Mice with ILC2-specific depletion of HTR2A(Il5^(cre/+)·Htr2a^(flox/flox)mice)abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation.In conclusion,serotonin and DOI could restrict the type 2 lung immune response,indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ILC2s.展开更多
基金This work was supported by National Natural Science Foundation of China(No.30671945)Science and Technology Commission of Shanghai Municipality(Nos.06JC14044,05ZR14055,054319928,04DZ14902)+2 种基金Shanghai Municipal Education(No.05BZ26)Shanghai Leading Academic Discipline Project(T0206)Science Foundation of Shanghai Institute of Immunology(No.07-A04,to Ningli Li).
文摘规章的 T 房间(Treg ) 在免疫系统动态平衡起重要作用，并且可以被压制涉及反肿瘤免疫的 Th1 免疫反应也涉及肿瘤免疫忍耐。我们以前报导了有稀释激活的自体同源的 T 房间的那免疫导致提高的反肿瘤免疫并且在调整 Th1 回答 invivo 上面。然而，内在的分子的机制很好没被理解。这里，我们证明 Tregfunction 是显著地， down 在老鼠调整了稀释激活的自体同源的 T 房间的那收到的免疫。我们发现那 Foxp3 表情从使免疫的老鼠在 CD4+CD25+ T 房间减少了。而且，从使免疫的老鼠获得的 CD4+CD25+Foxp3+ Treg 从天真的老鼠与那些相比展出了减少的免疫力的抑制能力。进一步的分析证明使免疫的鼠标的浆液包含 anti-CD25 抗体(大约 30 ng/ml， p【0.01 对控制) 的高水平。与在 Treg 的 down 规定的 anti-CD25 反应的一个角色一致，到天真的鼠标的从使免疫的鼠标的浆液的采纳转移在接受者鼠标在 Treg 人口和功能导致了重要减少。在使免疫的老鼠被触发 anti-CD25 反应能被 CD25 在激活的自体同源的 T 房间为免疫使用了的 ConA 被导致到高水平的事实解释。我们的结果第一次证明有稀释激活的自体同源的 T 房间的那免疫唤起 anti-CD25 抗体生产，它导致阻碍的 CD4+CD25+Foxp3+Treg 扩大和功能体内。我们建议那阻抑的 Treg 功能多半在使免疫的老鼠贡献提高的 Th1 反应并且是位于 boostedanti 肿瘤免疫下面的机制的至少部分。
文摘Adult stem/progenitor cells play important roles in tissue homeostasis and have important implications for regenerativemedicine.It was once thought that formation of new blood vessels in adult only occurs through angiogenesis,a processwhereby new vessels are formed from existing mature endothelial cells;while vasculogenesis,where new vessels arederived from differentiation of endothelial progenitor cells(EPCs),was thought to occur exclusively in embryos.Thediscovery of adult EPCs a few years ago has changed this old paradigm;and subsequent studies showed that EPCs maybe a promising tool for the treatment of vascular disorders.However,there have been conflicting reports on subtypes,surface markers,and functions of EPCs;and thus the exact origin and identity of EPCs remain to be defined.A commonapproach to obtain EPCs is to isolate and culture mononuclear cells from peripheral blood and to select adherent cells
文摘Prostate cancer is one of the leading health threats to man,and like many other cancers,early detection and treatment iscrucial to improving the prognosis of patients.Progression of the disease from noninvasive high-grade prostatic intraepi-thelial neoplasia (HGPIN) to invasive adenocarcinoma is linked to the action of a group of proteolytic enzymes calledmatrix metalloproteinases (MMPs),which digest various components of the extracellular matrix and thus open waysfor tumor metastasis.Previous studies have shown that one MMP,MMP-26,is expressed at a significantly higher levelin human prostate carcinoma than in normal prostate tissues,and that it appears to play an important role in promotinginvasion of prostate cancer cells [1].In this issue of Cell Research,Lee et al.report detailed analyses of the expressionpattern of MMP-26,along with its most potent endogenous inhibitor,TIMP-4 (TIMP stands for tissue inhibitor ofmetal-loproteinases),in a number of prostate cancer samples derived from human patients [2].Interestingly,they found
文摘Ovarian cancer is one of the most lethal malignancies in women.Identification of new therapeutic targets would provideopportunities for developing potentially more effective treatment regimes.In the July issue of Cell Research,Cao et al.reports that glycogen synthase kinase-3β(GSK-3β)plays an important role in positively regulating the proliferation ofhuman ovarian cancer cells,and thus it may represent such a target[1].GSK-3β is a serine/threonine kinase that is knownto be involved in regulation ofβ-catenin signaling,where it participates in the formation of a multi-component destructioncomplex that promotes the phosphorylation and subsequent degradation of β-catenin.Given that overactive β-cateninsignaling is involved in many forms of human cancer,this classic mode of GSK-3β action should qualify it as a'tumorsuppressor'.Intriguingly,however,two recent studies have implicated that GSK-3β may actually play a pro-tumor rolein pancreatic and colorectal cancers[2,3].Since ovarian tumors often exhibit increased expression of GSK-3β,theserecent findings prompted Cao et al.to examine the potential role of GSK-3β in ovarian cancer cells.
基金supported by the National Key Research and Development Program of China(2022YFA1303300,2021YFC2700200,2017YFA0504400)Chinese Academy of Sciences(“Strategic Priority Research Program”grants XDB37000000)+3 种基金the National Natural Science Foundation of China(31830109,31821004,91940305,31961133022,32101037,32271347,21933010,22203089)Science and Technology Commission of Shanghai Municipality(17JC1420100,2017SHZDZX01,19JC1410200,21YF1452700,21ZR1470500)the Young Elite Scientist Sponsorship Program of the China Association for Science and Technology(2021QNRC001)the Foundation of Key Laboratory of Gene Engineering of the Ministry of Education。
文摘PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.
文摘Proteasome-mediated degradation and autophagy are the two major pathways mediating the turnover of cellularproteins.The proteasomal pathway is known to be a highly specific and regulated process mediating the degradationof short-lived proteins such as many important factors involved in cellular signaling.In contrast,it is generally thoughtthat autophagy is rather nonselective as it is responsible for the bulk degradation of long-lived proteins and organelles.Challenging this general view,in this issue of Cell Research,Qing et al.report that selective degradation of the IκBkinase(IKK)triggered by the loss of Hsp90 function is mediated by autophagy[1].
基金This work was supported by the National Natural Science Foundation of China(91219304)National Basic Research Program of China(2010CB529705,2011CB510103,2014CB943100)the Council of Shanghai Municipal Government for Science and Technology.
文摘JMJD3(KDM6B)is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression.However,the function of JMJD3 in vivo is not well understood.Here we show that JMJD3 is highly expressed in cells of the chondrocyte lineage,especially in prehypertrophic and hypertrophic chondrocytes,during endochondral ossification.Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes,and thereby marked retardation of endochondral ossification in mice.Genetically,JMJD3 associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes.Biochemically,JMJD3 associates with and enhances RUNX2 activity by derepression of Runx2 and Ihh transcription throughits H3K27me3 demethylase activity.These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation.
基金supported by the Ministry of Science and Technology(2009CB522105)the Ministry of Health(2009ZX10004-308)of Chinasupport of the Science and Technology Commission of Shanghai Municipality(07pj14096).
文摘In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly understood.Here,we studied the infection and pathogenesis of a new 2009 pandemic strain,A/Wenshan/01/2009 H1N1,in China in human airway epithelial cell lines compared with contemporary seasonal H1N1 influenza virus.Our results showed that viral infection by the A/Wenshan H1N1 induced significant apoptotic cell death in both the human nasopharyngeal carcinoma cell line CNE-2Z and the human lung adenocarcinoma cell line A549.The A/Wenshan H1N1 virus enters both of these cell types more efficiently than the seasonal influenza virus.Viral entry in both cell lines was shown to be mediated by clathrin-and dynamin-dependent endocytosis.Therefore,we discovered that the 2009 pandemic H1N1 strain,A/Wenshan/01/2009,can induce apoptotic cell death in epithelial cells of the human respiratory tract,suggesting a molecular pathogenesis for the 2009 pandemic H1N1.
基金the Ministry of Science and Technology of China(2018YFA0507402)the National Natural Science Foundation of China(32000667)+5 种基金the Shanghai Science and Technology Innovation Action(21ZR1470600)the Youth Innovation Promotion Association of the Chinese Academy of Sciences(2022264)the National Natural Science Foundation of China(81771465 and 81930033)the Science and Technology Project of the Department of Education of Jiangxi Province(GJJ211248)the Division of Intramural Research,National Institute of Allergy and Infectious Diseases,National Institutes of Health(grant 1ZIA-Al-001169)the US-China Biomedical Collaborative Research Program(grant Al-129775).
文摘Group 2 innate lymphoid cells(ILC2s)are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13,which mediate the type 2 immune response.However,specific drug targets on lung ILC2s have rarely been reported.Previous studies have shown that type 2 cytokines,such as IL-5 and IL-13,are related to depression.Here,we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression.Interestingly,serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation.Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs.Furthermore,an HTR2A selective agonist(DOI)impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro.Mice with ILC2-specific depletion of HTR2A(Il5^(cre/+)·Htr2a^(flox/flox)mice)abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation.In conclusion,serotonin and DOI could restrict the type 2 lung immune response,indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ILC2s.
