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101.
Simon Borna Ales Drobek Jarmila Kralova Daniela Glatzova Iva Splichalova Matej Fabisik Jana Pokorna Tereza Skopcova Pavla Angelisova Veronika Kanderova Julia Starkova Petr Stanek Orest V. Matveichuk Nataliia Pavliuchenko Katarzyna Kwiatkowska Majd B. Protty Michael G. Tomlinson Meritxell Alberich‐Jorda Vladimir Korinek Tomas Brdicka 《Journal of cellular and molecular medicine》2020,24(2):1980-1992
WW domain binding protein 1‐like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6‐RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non‐haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4‐family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l‐deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis. 相似文献
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103.
David García‐Bernal Marta Palomo Carlos M. Martínez Jos E. Milln‐Rivero Ana I. García‐Guilln Miguel Blanquer Maribel Díaz‐Ricart Robert Sackstein Enric Carreras Jose M. Moraleda 《Journal of cellular and molecular medicine》2020,24(14):8031-8044
Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is an effective therapy for the treatment of high‐risk haematological malignant disorders and other life‐threatening haematological and genetic diseases. Acute graft‐versus‐host disease (aGvHD) remains the most frequent cause of non‐relapse mortality following allo‐HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi‐target drug successfully employed for prophylaxis and treatment of veno‐occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo‐HCT. Using a fully MHC‐mismatched murine model of allo‐HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD‐associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo‐HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte‐endothelial interactions by down‐regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo‐HCT, paving the way for new therapeutic approaches. 相似文献
104.
该研究探讨人尿源性干细胞(human urine-derived stem cells,hUSCs)及人脐带间充质干细胞(human umbilical cord mesenchymal stem cells,hUC-MSCs)的生物学性状差异。分离培养hUSCs及hUC-MSCs,显微镜下观察细胞形态,流式细胞术检测干细胞表面标记物,锥虫蓝拒染实验及克隆形成实验检测细胞增殖能力,划痕实验及Transwell迁移实验检测细胞迁移能力,碱性磷酸酶(alkaline phosphatase,ALP)染色、茜素红染色、油红O染色及阿利新蓝染色评估多向分化潜能。hUSCs为米粒状贴壁生长细胞,hUC-MSCs为长梭形贴壁细胞,呈旋涡状排列生长,两种细胞表型分析相似,均表达多种间充质干细胞标志物,但CD24在hUC-MSCs表达阳性,而CD105在hUSCs表达阳性。hUC-MSCs的增殖及迁移能力优于hUSCs,但后者的克隆形成能力更强。hUSCs及hUCMSCs都具有成骨、成脂、成软骨分化能力,hUC-MSCs的成骨能力强而hUSCs的成脂能力强。该研究成功分离培养出增殖能力强并具有多向分化潜能的hUSCs,该细胞与hUC-MSCs相比具有相似的生物学性状,可作为再生医学自体移植的理想种子细胞来源。 相似文献
105.
106.
107.
Clemens Alexander Boecker Mara A. Olenick Elizabeth R. Gallagher Michael E. Ward Erika L. F. Holzbaur 《Traffic (Copenhagen, Denmark)》2020,21(1):138-155
Induced pluripotent stem cells (iPSCs) hold promise to revolutionize studies of intracellular transport in live human neurons and to shed new light on the role of dysfunctional transport in neurodegenerative disorders. Here, we describe an approach for live imaging of axonal and dendritic transport in iPSC‐derived cortical neurons. We use transfection and transient expression of genetically‐encoded fluorescent markers to characterize the motility of Rab‐positive vesicles, including early, late and recycling endosomes, as well as autophagosomes and mitochondria in iPSC‐derived neurons. Comparing transport parameters of these organelles with data from primary rat hippocampal neurons, we uncover remarkable similarities. In addition, we generated lysosomal‐associated membrane protein 1 (LAMP1)‐enhanced green fluorescent protein (EGFP) knock‐in iPSCs and show that knock‐in neurons can be used to study the transport of endogenously labeled vesicles, as a parallel approach to the transient overexpression of fluorescently labeled organelle markers. 相似文献
108.
Kevin J. Parsons Kirsty McWhinnie Natalie Pilakouta Lynsey Walker 《Evolution & development》2020,22(1-2):56-70
The generation of variation is paramount for the action of natural selection. Although biologists are now moving beyond the idea that random mutation provides the sole source of variation for adaptive evolution, we still assume that variation occurs randomly. In this review, we discuss an alternative view for how phenotypic plasticity, which has become well accepted as a source of phenotypic variation within evolutionary biology, can generate nonrandom variation. Although phenotypic plasticity is often defined as a property of a genotype, we argue that it needs to be considered more explicitly as a property of developmental systems involving more than the genotype. We provide examples of where plasticity could be initiating developmental bias, either through direct active responses to similar stimuli across populations or as the result of programmed variation within developmental systems. Such biased variation can echo past adaptations that reflect the evolutionary history of a lineage but can also serve to initiate evolution when environments change. Such adaptive programs can remain latent for millions of years and allow development to harbor an array of complex adaptations that can initiate new bouts of evolution. Specifically, we address how ideas such as the flexible stem hypothesis and cryptic genetic variation overlap, how modularity among traits can direct the outcomes of plasticity, and how the structure of developmental signaling pathways is limited to a few outcomes. We highlight key questions throughout and conclude by providing suggestions for future research that can address how plasticity initiates and harbors developmental bias. 相似文献
109.
Haiping Zhang Bailian Cai Anke Geng Huanyin Tang Wenjun Zhang Sheng Li Ying Jiang Rong Tan Xiaoping Wan Zhiyong Mao 《Aging cell》2020,19(2)
The decline in DNA repair capacity contributes to the age‐associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age‐associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose‐derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17–25 years; old: 10 donors with ages ranging 50–59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double‐strand break (DSB) repair pathways—nonhomologous end joining (NHEJ) and homologous recombination (HR)—between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age‐associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs. 相似文献
110.
Xiaodong Mu Chieh Tseng William S. Hambright Polina Matre Chih‐Yi Lin Palas Chanda Wanqun Chen Jianhua Gu Sudheer Ravuri Yan Cui Ling Zhong John P. Cooke Laura J. Niedernhofer Paul D. Robbins Johnny Huard 《Aging cell》2020,19(8)
Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle‐derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24?/? (Z24?/?) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin‐induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F‐actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei‐induced cGAS‐Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24?/? mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria. 相似文献