Laia Richart, Mary-Loup Picod, M. Wassef, M. Macario, Setareh Aflaki, Marion A. Salvador, Julien Wicinski, V. Chevrier, S. Le Cam, Hanya A. Kamhawi, R. Castellano, Géraldine Guasch, E. Charafe-Jauffret, E. Heard, R. Margueron, C. Ginestier
X-chromosome inactivation (XCI) is triggered by up-regulation of XIST, which coats the chromosome in cis and promotes recruitment of chromatin modifiers that transform the X into a silent heterochromatic domain. Whether XIST plays a role beyond initiation of XCI is unclear. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSC) and, upon oncogenic transformation, promotes emergence of highly metastatic carcinomas. On the Xi, XIST-deficient MaSC display epigenetic erosion and reactivation of genes overlapping Polycomb domains. Among reactivated loci we identify MED14 , a critical backbone of Mediator, and show that MED14 overdosage is sufficient to explain how defective XCI maintenance can stabilize MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We conclude that XIST is a gatekeeper of mammary epithelium homeostasis, thus unveiling a new paradigm in the control of somatic cell identity with potential consequences in our understanding of gender-specific malignancies.
{"title":"Loss of XIST Impairs Human Mammary Stem Cell Differentiation and Increases Tumorigenicity Through Enhancer and Mediator Complex Hyperactivation","authors":"Laia Richart, Mary-Loup Picod, M. Wassef, M. Macario, Setareh Aflaki, Marion A. Salvador, Julien Wicinski, V. Chevrier, S. Le Cam, Hanya A. Kamhawi, R. Castellano, Géraldine Guasch, E. Charafe-Jauffret, E. Heard, R. Margueron, C. Ginestier","doi":"10.2139/ssrn.3809998","DOIUrl":"https://doi.org/10.2139/ssrn.3809998","url":null,"abstract":"X-chromosome inactivation (XCI) is triggered by up-regulation of XIST, which coats the chromosome in cis and promotes recruitment of chromatin modifiers that transform the X into a silent heterochromatic domain. Whether XIST plays a role beyond initiation of XCI is unclear. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSC) and, upon oncogenic transformation, promotes emergence of highly metastatic carcinomas. On the Xi, XIST-deficient MaSC display epigenetic erosion and reactivation of genes overlapping Polycomb domains. Among reactivated loci we identify MED14 , a critical backbone of Mediator, and show that MED14 overdosage is sufficient to explain how defective XCI maintenance can stabilize MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We conclude that XIST is a gatekeeper of mammary epithelium homeostasis, thus unveiling a new paradigm in the control of somatic cell identity with potential consequences in our understanding of gender-specific malignancies.","PeriodicalId":228505,"journal":{"name":"MatSciRN: Stem Cell Bioengineering (Topic)","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114364623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Optogenetics is an emerging branch of biology that combines genetics and optics to achieve precise light control of specific cells in organisms. It is a method of studying excitable cells that uses proteins that are embedded in the cell membrane and are activated by light (i.e. “opto”). Such proteins (opsins) are found in most animals in the retina of the eyes, as well as in some plants, such as green algae. In order to integrate photoactivated proteins into neuronal membranes, it is necessary to introduce rhodopsin genes obtained from other organisms into neurons, hence the “genetics”. Optogenetics is widely used in the field of modern neurobiology, and plays an essential role in the study of the mechanism of neural circuits, behaviors, central nervous system diseases, and mental disorders. Based on the development of optogenetics technology, this paper introduces its optimization and localization expression, which not only provides references for the research and development of optogenetics, but also provides the possibility for in-depth research and treatment of neurological diseases.
{"title":"Optogenetics: The Key to Deciphering and Curing Neurological Diseases","authors":"Fuzhou Wang","doi":"10.15354/si.20.re081","DOIUrl":"https://doi.org/10.15354/si.20.re081","url":null,"abstract":"Optogenetics is an emerging branch of biology that combines genetics and optics to achieve precise light control of specific cells in organisms. It is a method of studying excitable cells that uses proteins that are embedded in the cell membrane and are activated by light (i.e. “opto”). Such proteins (opsins) are found in most animals in the retina of the eyes, as well as in some plants, such as green algae. In order to integrate photoactivated proteins into neuronal membranes, it is necessary to introduce rhodopsin genes obtained from other organisms into neurons, hence the “genetics”. Optogenetics is widely used in the field of modern neurobiology, and plays an essential role in the study of the mechanism of neural circuits, behaviors, central nervous system diseases, and mental disorders. Based on the development of optogenetics technology, this paper introduces its optimization and localization expression, which not only provides references for the research and development of optogenetics, but also provides the possibility for in-depth research and treatment of neurological diseases.","PeriodicalId":228505,"journal":{"name":"MatSciRN: Stem Cell Bioengineering (Topic)","volume":"30 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115754019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem cell therapies are unsatisfactory due to poor cell survival and engraftment. Stem cell used for therapy must be properly “tuned” for a harsh in vivo environment. Herein, we report that transfer of exogenous mitochondria (mito) to adipose-derived mesenchymal stem cells (ADSCs) can effectively boost their energy levels, enabling efficient cell engraftment. Importantly, the entire process of exogeneous mitochondrial endocytosis is captured by high-content live-cell imaging. Mitochondrial transfer leads to acutely enhanced bioenergetics, with nearly 17% of higher adenosine 5′-triphosphate (ATP) levels in ADSCs treated with high mitochondrial dosage, and further results in altered secretome profiles of ADSCs. Mitochondrial transfer also induced the expression of 334 mRNAs in ADSCs which are mainly involved in signaling pathways related to DNA replication and cell cycle. We propose that increase in ATP and cyclin-dependent kinase (CDK) 1 and 2 expression might be responsible for promoting enhanced proliferation, migration and differentiation of ADSCs in vitro. More importantly, mito-transferred ADSCs display prolonged cell survival, engraftment and horizontal transfer of exogenous mitochondria to surrounding cells in a full-thickness skin defect rat model with improved skin repair compared with non-treated ADSCs. These results demonstrate that intracellular mitochondrial transplantation is a promising strategy to engineer stem cells for tissue regeneration.
{"title":"Scale-Up Engineering Super-Energetic Adipose-Derived Mesenchymal Stem Cells with Mitochondrial Transplantation for Tissue Regeneration","authors":"Xudong Yao, Yuanzhu Ma, Youguo Liao, Qiulin He, Hongwei Wu, Junxin Lin, Wenyan Zhou, Zongsheng Jiang, Wei Wei, Xiaozhao Wang, M. Björklund, H. Ouyang","doi":"10.2139/ssrn.3855761","DOIUrl":"https://doi.org/10.2139/ssrn.3855761","url":null,"abstract":"Stem cell therapies are unsatisfactory due to poor cell survival and engraftment. Stem cell used for therapy must be properly “tuned” for a harsh in vivo environment. Herein, we report that transfer of exogenous mitochondria (mito) to adipose-derived mesenchymal stem cells (ADSCs) can effectively boost their energy levels, enabling efficient cell engraftment. Importantly, the entire process of exogeneous mitochondrial endocytosis is captured by high-content live-cell imaging. Mitochondrial transfer leads to acutely enhanced bioenergetics, with nearly 17% of higher adenosine 5′-triphosphate (ATP) levels in ADSCs treated with high mitochondrial dosage, and further results in altered secretome profiles of ADSCs. Mitochondrial transfer also induced the expression of 334 mRNAs in ADSCs which are mainly involved in signaling pathways related to DNA replication and cell cycle. We propose that increase in ATP and cyclin-dependent kinase (CDK) 1 and 2 expression might be responsible for promoting enhanced proliferation, migration and differentiation of ADSCs in vitro. More importantly, mito-transferred ADSCs display prolonged cell survival, engraftment and horizontal transfer of exogenous mitochondria to surrounding cells in a full-thickness skin defect rat model with improved skin repair compared with non-treated ADSCs. These results demonstrate that intracellular mitochondrial transplantation is a promising strategy to engineer stem cells for tissue regeneration.","PeriodicalId":228505,"journal":{"name":"MatSciRN: Stem Cell Bioengineering (Topic)","volume":"28 10","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114033267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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