The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emer...The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emerged as a viable candidate in the mouse. To explore the relationship between Dlk1-Dio3 expression and developmental potential more fully, we used murine ear mesenchymal stem cells (mEMSC) for iPS cell induction. Mouse EMSC are easily obtained and share functional characteristics with embryonic stem (ES) cells and therefore, may be a reliable non-embryonic source for iPS cell production. We report that mEMSC express high levels of Gtl2, a maternally expressed gene within the Dlk1-Dio3 imprinted cluster. Moreover, mEMSC produce Gtl2 expressing (Gtl2on) iPSC clones that share functional characteristics with ES cell clones. The production of Gtl2on iPS cell clones from mEMSC provides a new model with which to investigate the regulation of Dlk1-Dio3 cluster activity during direct cell reprogramming.展开更多
Fungal infections cause~1.5 million deaths each year worldwide,and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria.The major reasons for the high mortality of candidi...Fungal infections cause~1.5 million deaths each year worldwide,and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria.The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species.Therefore,a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies.Here,we report that DOCK2(dedicator of cytokinesis 2)promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages.DOCK2-deficient macrophages exhibit decreased RAC GTPase(Rac family small GTPase)activation and ROS(reactive oxygen species)production,which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways.Mechanistically,after fungal stimulation,activated SYK(spleen-associated tyrosine kinase)phosphorylates DOCK2 at tyrosine 985 and 1405,which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation.Importantly,nanoparticle-mediated delivery of in vitro transcribed(IVT)Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo.Taken together,this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.展开更多
文摘The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emerged as a viable candidate in the mouse. To explore the relationship between Dlk1-Dio3 expression and developmental potential more fully, we used murine ear mesenchymal stem cells (mEMSC) for iPS cell induction. Mouse EMSC are easily obtained and share functional characteristics with embryonic stem (ES) cells and therefore, may be a reliable non-embryonic source for iPS cell production. We report that mEMSC express high levels of Gtl2, a maternally expressed gene within the Dlk1-Dio3 imprinted cluster. Moreover, mEMSC produce Gtl2 expressing (Gtl2on) iPSC clones that share functional characteristics with ES cell clones. The production of Gtl2on iPS cell clones from mEMSC provides a new model with which to investigate the regulation of Dlk1-Dio3 cluster activity during direct cell reprogramming.
基金supported by a grant from the National Key Research and Development Program of China (2020YFA0710700 to CHW)the National Natural Science Foundation of China (Grant No.82101859 to WWS)+4 种基金the Original Exploration Program of National Natural Science Foundation of China (82150102,to CHW)the Key Research and Development Program of Sichuan Province (22ZDYF3738,to CHW)the Fundamental Research Funds for the Central Universities,HUST (2021GCRC031 to CHW)the National Natural Science Foundation of China (31870165 to BZ)the Shenzhen Science and Technology Innovation Fund (JCYJ20210324115811032 to BZ).
文摘Fungal infections cause~1.5 million deaths each year worldwide,and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria.The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species.Therefore,a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies.Here,we report that DOCK2(dedicator of cytokinesis 2)promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages.DOCK2-deficient macrophages exhibit decreased RAC GTPase(Rac family small GTPase)activation and ROS(reactive oxygen species)production,which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways.Mechanistically,after fungal stimulation,activated SYK(spleen-associated tyrosine kinase)phosphorylates DOCK2 at tyrosine 985 and 1405,which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation.Importantly,nanoparticle-mediated delivery of in vitro transcribed(IVT)Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo.Taken together,this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.
