Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed t...Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.展开更多
Small cell lung cancer(SCLC)is a phenotypically heterogeneous disease with an extremely poor prognosis,which is mainly attributed to the rapid development of resistance to chemotherapy.However,the relation between the...Small cell lung cancer(SCLC)is a phenotypically heterogeneous disease with an extremely poor prognosis,which is mainly attributed to the rapid development of resistance to chemotherapy.However,the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear.Through comprehensive bioinformatic analyses,we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy.Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant.Mechanistically,activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance.Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors.Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance,which holds important clinical implications for improving SCLC treatment.展开更多
Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms we...Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.展开更多
Dear Editor,Pathogenic fungi often undergo rapid morphological transitions to adapt to dynamic environments during infections and in natural habitats(Biswas et al.,2007;Prasad and Tippana,2023).These phenotypic transi...Dear Editor,Pathogenic fungi often undergo rapid morphological transitions to adapt to dynamic environments during infections and in natural habitats(Biswas et al.,2007;Prasad and Tippana,2023).These phenotypic transitions are primarily driven by environmental cues through nongenetic alterations,including epigenetic,transcriptional,and post-transcriptional modifications(Biswas et al.,2007).展开更多
Single-cell analysis of phenotypic plasticity could improve the development of more effective therapeutics.Still,the development of tools to measure single-cell heterogeneity has lagged due to difficulties in manipula...Single-cell analysis of phenotypic plasticity could improve the development of more effective therapeutics.Still,the development of tools to measure single-cell heterogeneity has lagged due to difficulties in manipulating and culturing single cells.Here,we describe a single-cell culture and phenotyping platform that employs a starburst microfluidic network and automatic liquid handling system to capture single cells for long-term culture and multi-dimensional analysis and quantify their clonal properties via their surface biomarker and secreted cytokine/growth factor profiles.Studies performed on this platform found that cells derived from single-cell cultures maintained phenotypic equilibria similar to their parental populations.Single-cell cultures exposed to chemotherapeutic drugs stochastically disrupted this balance to favor stem-like cells.They had enhanced expression of mRNAs and secreted factors associated with cell signaling,survival,and differentiation.This single-cell analysis approach can be extended to analyze more complex phenotypes and screen responses to therapeutic targets.展开更多
A coordinated interaction between osteogenesis and osteoimmune microenvironment is essential for successful bone healing.In particular,macrophages play a central regulatory role in all stages of bone repair.Depending ...A coordinated interaction between osteogenesis and osteoimmune microenvironment is essential for successful bone healing.In particular,macrophages play a central regulatory role in all stages of bone repair.Depending on the signals they sense,these highly plastic cells can mediate the host immune response against the exterior signals of molecular stimuli and implanted scaffolds,to exert regenerative potency to a varying extent.In this article,we first encapsulate the immunomodulatory functions of macrophages during bone regeneration into three aspects,as sweeper,mediator and instructor.We introduce the phagocytic role of macrophages in different bone healing periods(‘sweeper’)and overview a variety of paracrine cytokines released by macrophages either mediating cell mobilisation,vascularisation and matrix remodelling(‘mediator’),or directly driving the osteogenic differentiation of bone progenitors and bone repair(‘instructor’).Then,we systematically classify and discuss the emerging engineering strategies to recruit,activate and modulate the phenotype transition of macrophages,to exploit the power of endogenous macrophages to enhance the performance of engineered bone tissue.展开更多
基金the support of the National Natural Science Foundation of China (Grant No.82272503)Natural Science Foundation of Zhejiang Province (Grant No. LQN25H060006)
文摘Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.
基金supported by the National Natural Science Foundation of China(82030083 to H.J.,81871875 to L.H.)the National Basic Research Program of China(2017YFA0505501 to H.J.+8 种基金2020YFA0803300 to H.J.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19020201 to H.J.)the National Natural Science Foundation of China(81872312 to H.J.,82011540007 to H.J.,31621003 to H.J.,81402371 to Y.J.,81802279 to H.H.,81902326 to X.W.,81602443 to X.L.)the Basic Frontier Scientific Research Program of Chinese Academy of Science(ZDBSLY-SM006 to H.J.)the International Cooperation Project of Chinese Academy of Sciences(153D31KYSB20190035 to H.J.)the Youth Innovation Promotion Association CAS(Y919S31371 to X.W.)the Natural Science Foundation of Hunan Province,China(2019JJ50550 to X.L.)Clinical Medical Technology Innovation Guide Project of Hunan(2020SK51827 to X.L.)Project of Scientific Research Plan of Hunan Provincial Health Commission(202103100127 to X.L.)。
文摘Small cell lung cancer(SCLC)is a phenotypically heterogeneous disease with an extremely poor prognosis,which is mainly attributed to the rapid development of resistance to chemotherapy.However,the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear.Through comprehensive bioinformatic analyses,we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy.Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant.Mechanistically,activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance.Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors.Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance,which holds important clinical implications for improving SCLC treatment.
文摘Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.
基金supported by the National Key Research and Development Program of China(2022YFC2303000,2021YFC2300400)the National Natural Science Foundation of China(31930005,82272359,32170194,32170193,82202546)the China Postdoctoral Science Foundation(2023M730684,2022M720804)。
文摘Dear Editor,Pathogenic fungi often undergo rapid morphological transitions to adapt to dynamic environments during infections and in natural habitats(Biswas et al.,2007;Prasad and Tippana,2023).These phenotypic transitions are primarily driven by environmental cues through nongenetic alterations,including epigenetic,transcriptional,and post-transcriptional modifications(Biswas et al.,2007).
基金supported by grants from the National Natural Science Foundation of China(Nos.82072087,31970893,and 32270976)Science and Technology Projects in Guangzhou(No.202206010087,China)+2 种基金Natural Science Foundation of Guangdong Province(Nos.2022A1515012541 and 2024A1515011932,China)the Fundamental Research Funds for the Central Universities(No.19ykzd39,China)and the 111 Project(No.B12003,and B13037,China)the China Postdoctoral Science Foundation(No.2022M723661).
文摘Single-cell analysis of phenotypic plasticity could improve the development of more effective therapeutics.Still,the development of tools to measure single-cell heterogeneity has lagged due to difficulties in manipulating and culturing single cells.Here,we describe a single-cell culture and phenotyping platform that employs a starburst microfluidic network and automatic liquid handling system to capture single cells for long-term culture and multi-dimensional analysis and quantify their clonal properties via their surface biomarker and secreted cytokine/growth factor profiles.Studies performed on this platform found that cells derived from single-cell cultures maintained phenotypic equilibria similar to their parental populations.Single-cell cultures exposed to chemotherapeutic drugs stochastically disrupted this balance to favor stem-like cells.They had enhanced expression of mRNAs and secreted factors associated with cell signaling,survival,and differentiation.This single-cell analysis approach can be extended to analyze more complex phenotypes and screen responses to therapeutic targets.
基金the funding grants from Fundo para o Desenvolvimento das Ciencias e da Tecnologia,Macao SAR(0018/2019/AFJ)the University of Macao(MYRG2019-00080-ICMS).
文摘A coordinated interaction between osteogenesis and osteoimmune microenvironment is essential for successful bone healing.In particular,macrophages play a central regulatory role in all stages of bone repair.Depending on the signals they sense,these highly plastic cells can mediate the host immune response against the exterior signals of molecular stimuli and implanted scaffolds,to exert regenerative potency to a varying extent.In this article,we first encapsulate the immunomodulatory functions of macrophages during bone regeneration into three aspects,as sweeper,mediator and instructor.We introduce the phagocytic role of macrophages in different bone healing periods(‘sweeper’)and overview a variety of paracrine cytokines released by macrophages either mediating cell mobilisation,vascularisation and matrix remodelling(‘mediator’),or directly driving the osteogenic differentiation of bone progenitors and bone repair(‘instructor’).Then,we systematically classify and discuss the emerging engineering strategies to recruit,activate and modulate the phenotype transition of macrophages,to exploit the power of endogenous macrophages to enhance the performance of engineered bone tissue.
