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An acute immune response underlies the benefit of cardiac stem cell therapy 期刊论文
NATURE, 2020, 577 (7790) : 405-+
作者:  Schmacke, Niklas A.;  Hornung, Veit
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day(1,2), despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect(3). The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury(4,5). Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2(+) and CX3CR1(+) macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2(+) and CX3CR1(+) macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.


  
Senolytic CAR T cells reverse senescence-associated pathologies 期刊论文
NATURE, 2020, 583 (7814) : 127-+
作者:  Cortez, Jessica T.;  Montauti, Elena;  Shifrut, Eric;  Gatchalian, Jovylyn;  Zhang, Yusi;  Shaked, Oren;  Xu, Yuanming;  Roth, Theodore L.;  Simeonov, Dimitre R.;  Zhang, Yana;  Chen, Siqi;  Li, Zhongmei;  Woo, Jonathan M.;  Ho, Josephine;  Vogel, Ian A.
收藏  |  浏览/下载:86/0  |  提交时间:2020/07/03

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment(1,2). Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells(3,4)and has a beneficial role in wound-healing responses(5,6). Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis(1,7). Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity(1,2,8-10). Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)(11)as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.


Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.


  
Liquid flow and control without solid walls 期刊论文
NATURE, 2020, 581 (7806) : 58-+
作者:  Hellmuth, Susanne;  Stemmann, Olaf
收藏  |  浏览/下载:50/0  |  提交时间:2020/07/03

Wall-free liquid channels surrounded by an immiscible magnetic liquid can be used to create liquid circuitry or to transport human blood without damaging the blood cells by moving permanent magnets.


When miniaturizing fluidic circuitry, the solid walls of the fluid channels become increasingly important(1) because they limit the flow rates achievable for a given pressure drop, and they are prone to fouling(2). Approaches for reducing the wall interactions include hydrophobic coatings(3), liquid-infused porous surfaces(4-6), nanoparticle surfactant jamming(7), changes to surface electronic structure(8), electrowetting(9,10), surface tension pinning(11,12) and use of atomically flat channels(13). A better solution may be to avoid the solid walls altogether. Droplet microfluidics and sheath flow achieve this but require continuous flow of the central liquid and the surrounding liquid(1,14). Here we demonstrate an approach in which aqueous liquid channels are surrounded by an immiscible magnetic liquid, both of which are stabilized by a quadrupolar magnetic field. This creates self-healing, non-clogging, anti-fouling and near-frictionless liquid-in-liquid fluidic channels. Manipulation of the field provides flow control, such as valving, splitting, merging and pumping. The latter is achieved by moving permanent magnets that have no physical contact with the liquid channel. We show that this magnetostaltic pumping method can be used to transport whole human blood with very little damage due to shear forces. Haemolysis (rupture of blood cells) is reduced by an order of magnitude compared with traditional peristaltic pumping, in which blood is mechanically squeezed through a plastic tube. Our liquid-in-liquid approach provides new ways to transport delicate liquids, particularly when scaling channels down to the micrometre scale, with no need for high pressures, and could also be used for microfluidic circuitry.


  
Metabolites released from apoptotic cells act as tissue messengers 期刊论文
NATURE, 2020
作者:  Chica, Daniel G.;  He, Yihui;  McCall, Kyle M.;  Chung, Duck Young;  Pak, Rahmi O.;  Trimarchi, Giancarlo;  Liu, Zhifu;  De Lurgio, Patrick M.;  Wessels, Bruce W.;  Kanatzidis, Mercouri G.
收藏  |  浏览/下载:32/0  |  提交时间:2020/07/03

Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body(1), and regulates inflammation, cell proliferation, and tissue regeneration(2-4). How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as '  good-bye'  signals to actively modulate outcomes in tissues.


Apoptotic cells communicate with neighbouring cells by the regulated release of specific metabolites, and a cocktail of select apoptotic metabolites reduces disease severity in mouse models of inflammatory arthritis and lung transplant rejection.


  
Lipid availability determines fate of skeletal progenitor cells via SOX9 期刊论文
NATURE, 2020
作者:  Obata, Yuuki;  Castano, Alvaro;  Boeing, Stefan;  Bon-Frauches, Ana Carina;  Fung, Candice;  Fallesen, Todd;  De Aguero, Mercedes Gomez;  Yilmaz, Bahtiyar;  Lopes, Rita;  Huseynova, Almaz;  Horswell, Stuart;  Maradana, Muralidhara Rao;  Boesmans, Werend;  Vanden Berghe, Pieter;  Murray, Andrew J.;  Stockinger, Brigitta;  Macpherson, Andrew J.;  Pachnis, Vassilis
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

Lipid starvation results in skeletal progenitors favouring commitment to chondrogenic over osteogenic fate, a process mediated by FOXO transcription factors and SOX9.


The avascular nature of cartilage makes it a unique tissue(1-4), but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.


  
Developing a restoration narrative: A pathway towards system-wide healing and a restorative culture 期刊论文
ECOLOGICAL ECONOMICS, 2020, 168
作者:  Blignaut, James;  Aronson, James
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/02
Ceteris parthus  Natural capital  Restoration narrative  Restorative culture  System-wide healing  Wicked systems  
TGF-beta orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1 期刊论文
NATURE, 2020, 577 (7791) : 566-+
作者:  Su, Jie;  Morgani, Sophie M.;  David, Charles J.;  Wang, Qiong;  Er, Ekrem Emrah;  Huang, Yun-Han;  Basnet, Harihar;  Zou, Yilong;  Shu, Weiping;  Soni, Rajesh K.;  Hendrickson, Ronald C.;  Hadjantonakis, Anna-Katerina;  Massague, Joan
收藏  |  浏览/下载:31/0  |  提交时间:2020/07/03

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer(1-4). EMTs are driven by SNAIL, ZEB and TWIST transcription factors(5,6) together with microRNAs that balance this regulatory network(7,8). Transforming growth factor beta (TGF-beta) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-beta signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer(4,11). TGF-beta depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12-19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector(20,21), as a key partner of TGF-beta-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-beta-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-beta-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-beta pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.


RAS and TGF-beta pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1.


  
U-Th Dating of Syntectonic Calcite Veins Reveals the Dynamic Nature of Fracture Cementation and Healing in Faults 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2019, 46 (22) : 12900-12908
作者:  Williams, Randolph T.;  Mozley, Peter S.;  Sharp, Warren D.;  Goodwin, Laurel B.
收藏  |  浏览/下载:13/0  |  提交时间:2020/02/17
faults  earthquakes  healing  sealing  fractures  veins  
Observed changes in Brewer?Dobson circulation for 1980?2018 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2019, 14 (11)
作者:  Fu, Qiang;  Solomon, Susan;  Pahlavan, Hamid A.;  Lin, Pu
收藏  |  浏览/下载:14/0  |  提交时间:2020/02/17
Brewer?Dobson circulation  ozone depletion and healing  MSU  AMSU  
Consequences of long-term infrastructure decisions?the case of self-healing roads and their CO2 emissions 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2019, 14 (11)
作者:  Maria Rodriguez-Alloza, Ana;  Heihsel, Michael;  Fry, Jacob;  Gallego, Juan;  Geschke, Arne;  Wood, Richard;  Lenzen, Manfred
收藏  |  浏览/下载:49/0  |  提交时间:2020/02/17
life cycle assessment  hybrid LCA  input?output analysis  self-healing asphalt  road  climate change