An ongoing outbreak of COVID-19 has exhibited significant threats around the world. We found a significant decrease of T lymphocyte subsets and an increase of inflammatory cytokines of hospitalized ...patients with COVID-19 in clinical practice.
We conducted a retrospective, single-center observational study of in-hospital adult patients with confirmed COVID-19 in Hubei Provincial Hospital of traditional Chinese and Western medicine (Wuhan, China) by Mar 1, 2020. Demographic, clinical, laboratory information, especially T lymphocyte subsets and inflammatory cytokines were reported. For patients who died or discharge from hospital, the associations of T lymphocyte subsets on admission were evaluated by univariate logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs), warning values to predict in-hospital death were assessed by Receiver Operator Characteristic (ROC) curves.
A total of 187 patients were enrolled in our study from Dec 26, 2019 to Mar 1, 2020, of whom 145 were survivors (discharge = 117) or non-survivors (in-hospital death ==28). All patients exhibited a significant drop of T lymphocyte subsets counts with remarkably increasing concentrations of SAA, CRP, IL-6, and IL-10 compared to normal values. The median concentrations of SAA and CRP in critically-ill patients were nearly 4- and 10-fold than those of mild-ill patients, respectively. As the severity of COVID-19 getting worse, the counts of T lymphocyte drop lower.28 patients died in hospital, the median lymphocyte, CD3+ T-cell, CD4+ T-cell, CD8+ T-cell and B-cell were significantly lower than other patients. Lower counts (/uL) of T lymphocyte subsets lymphocyte (<500), CD3+T-cell (<200), CD4+ T-cell (<100), CD8+ T-cell (<100) and B-cell (<50) were associated with higher risks of in-hospital death of CIVID-19. The warning values to predict in-hospital death of lymphocyte, CD3+ T-cell, CD4+ T-cell, CD8+ T-cell, and B-cell were 559, 235, 104, 85 and 82, respectively.
We find a significant decrease of T lymphocyte subset is positively correlated with in-hospital death and severity of illness. The decreased levels of T lymphocyte subsets reported in our study were similar with SARS but not common among other virus infection, which may be possible biomarkers for early diagnosis of COVID-19. Our findings may shed light on early warning of high risks of mortality and help early intervention and treatment of COVID-19.
Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to ...be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated β-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.
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•Loss of KDM4B exacerbates bone-fat imbalance in skeletal aging and osteoporosis•Loss of KDM4B impairs MSC self-renewal and promotes MSC exhaustion•Loss of KDM4B induces senescence-associated heterochromatin foci formation•KDM4B is required for the anabolic effects of parathyroid hormone
Deng et al. show that loss of the epigenetic factor KDM4B in mesenchymal stromal cells exacerbates skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3, suggesting that targeting KDM4B might provide a new strategy for preventing and treating skeletal aging and osteoporosis.
Mesenchymal stem cells (MSCs) are the focus of intensive efforts worldwide directed not only at elucidating their nature and unique properties but also developing cell-based therapies for a diverse ...range of diseases. More than three decades have passed since the original formulation of the concept, revolutionary at the time, that multiple connective tissues could emanate from a common progenitor or stem cell retained in the postnatal bone marrow. Despite the many important advances made since that time, substantial ambiguities still plague the field regarding the nature, identity, function, mode of isolation and experimental handling of MSCs. These uncertainties have a major impact on their envisioned therapeutic use.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive tumor and the sixth most common cancer worldwide. Current treatment strategies for HNSCC are surgery, radiotherapy, ...chemotherapy, immunotherapy or combinatorial therapies. However, the overall 5-year survival rate of HNSCC patients remains at about 50%. Cancer stem cells (CSCs), a small population among tumor cells, are able to self-renew and differentiate into different tumor cell types in a hierarchical manner, similar to normal tissue. In HNSCC, CSCs are proposed to be responsible for tumor initiation, progression, metastasis, drug resistance, and recurrence. In this review, we discuss the molecular and cellular characteristics of CSCs in HNSCC. We summarize current approaches used in the literature for identification of HNSCC CSCs, and mechanisms required for CSC regulation. We also highlight the role of CSCs in treatment failure and therapeutic targeting options for eliminating CSCs in HNSCC.
The high prevalence of cartilage diseases and limited treatment options create a significant biomedical burden. Due to the inability of cartilage to regenerate itself, introducing chondrocyte ...progenitor cells to the affected site is of significant interest in cartilage regenerative therapies. Tissue engineering approaches using human mesenchymal stem cells (MSCs) are promising due to their chondrogenic potential, but a comprehensive understanding of the mechanisms governing the fate of MSCs is required for precise therapeutic applications in cartilage regeneration. TGF‐β is known to induce chondrogenesis by activating SMAD signaling pathway and upregulating chondrogenic genes such as SOX9; however, the epigenetic regulation of TGF‐β‐mediated chondrogenesis is not understood. In this report, we found that TGF‐β dramatically induced the expression of KDM4B in MSCs. When KDM4B was overexpressed, chondrogenic differentiation was significantly enhanced while KDM4B depletion by shRNA led to a significant reduction in chondrogenic potential. Mechanistically, upon TGF‐β stimulation, KDM4B was recruited to the SOX9 promoter, removed the silencing H3K9me3 marks, and activated the transcription of SOX9. Furthermore, KDM4B depletion reduced the occupancy of SMAD3 in the SOX9 promoter, suggesting that KDM4B is required for SMAD‐dependent coactivation of SOX9. Our results demonstrate the critical role of KDM4B in the epigenetic regulation of TGF‐β‐mediated chondrogenic differentiation of MSCs. Since histone demethylases are chemically modifiable, KDM4B may be a novel therapeutic target in cartilage regenerative therapy. Stem Cells 2016;34:711–719
Epigenetic regulation of TGF‐directed chondrogenesis and its future in cartilage regeneration
Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation ...(H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells. In vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated cancer stem cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells.
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•KDM4A controls invasive growth and immune evasion during SCC development•KDM4A loss induces liquid-like HP1γ puncta and DNA replication stress in SCC•KDM4A loss activates tumor-cell-intrinsic immunity through replication stress•Targeting KDM4A enhances anti-PD-1 therapy and eliminates cancer stem cells
Zhang et al. show that targeting KDM4A activated tumor-cell-intrinsic immunity by inducing heterochromatin compaction and replication stress. The combination of PD1 blockade and KDM4A inhibition potently inhibited SCC growth and lymph node metastasis by recruiting new CD8+ T cells and eliminating cancer stem cells.
The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide ...downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the “alternative Wnt-YAP/TAZ signaling axis” that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.
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•Wnt ligands promote YAP/TAZ activation via the alternative Wnt signaling pathway•Alternative Wnt-YAP/TAZ signaling consists of Wnt-FZD/ROR-Gα12/13-Rho-Lats1/2-YAP/TAZ•YAP/TAZ mediate alternative Wnt signaling-induced osteogenesis and cell migration•YAP/TAZ antagonize Wnt/β-catenin signaling by inducing secreted Wnt inhibitors
The transcriptional regulators YAP and TAZ are found to be the key downstream effectors of alternative Wnt signaling to mediate the effects of Wnt ligands on cell migration and osteogenic differentiation, as well as negative regulation of canonical Wnt/β-catenin signaling.
Mammalian cells are surrounded by neighbouring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes
. The ...Hippo pathway effectors YAP (also known as YAP1) and TAZ (also known as WWTR1) are regulated by mechanical cues and mediate cellular responses to ECM stiffness
. Here we identified the Ras-related GTPase RAP2 as a key intracellular signal transducer that relays ECM rigidity signals to control mechanosensitive cellular activities through YAP and TAZ. RAP2 is activated by low ECM stiffness, and deletion of RAP2 blocks the regulation of YAP and TAZ by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase Cγ1 (PLCγ1) to influence levels of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid, which activates RAP2 through PDZGEF1 and PDZGEF2 (also known as RAPGEF2 and RAPGEF6). At low stiffness, active RAP2 binds to and stimulates MAP4K4, MAP4K6, MAP4K7 and ARHGAP29, resulting in activation of LATS1 and LATS2 and inhibition of YAP and TAZ. RAP2, YAP and TAZ have pivotal roles in mechanoregulated transcription, as deletion of YAP and TAZ abolishes the ECM stiffness-responsive transcriptome. Our findings show that RAP2 is a molecular switch in mechanotransduction, thereby defining a mechanosignalling pathway from ECM stiffness to the nucleus.
Mesenchymal stem cell (MSC)-based transplantation is a promising therapeutic approach for bone regeneration and repair. In the realm of therapeutic bone regeneration, the defect or injured tissues ...are frequently inflamed with an abnormal expression of inflammatory mediators. Growing evidence suggests that proinflammatory cytokines inhibit osteogenic differentiation and bone formation. Thus, for successful MSC-mediated repair, it is important to overcome the inflammation-mediated inhibition of tissue regeneration. In this study, using genetic and chemical approaches, we found that proinflammatory cytokines TNF and IL-17 stimulated IκB kinase (IKK)–NF-κB and impaired osteogenic differentiation of MSCs. In contrast, the inhibition of IKK–NF-κB significantly enhanced MSC-mediated bone formation. Mechanistically, we found that IKK–NF-κB activation promoted β-catenin ubiquitination and degradation through induction of Smurf1 and Smurf2. To translate our basic findings to potential clinic applications, we showed that the IKK small molecule inhibitor, IKKVI, enhanced osteogenic differentiation of MSCs. More importantly, the delivery of IKKVI promoted MSC-mediated craniofacial bone regeneration and repair in vivo. Considering the well established role of NF-κB in inflammation and infection, our results suggest that targeting IKK–NF-κB may have dual benefits in enhancing bone regeneration and repair and inhibiting inflammation, and this concept may also have applicability in many other tissue regeneration situations.
Editorial The sense of light is the first sensation the human body develops. The importance of light is self-evident. However, we all know that the light we can see and perceive covers only a small ...section of the spectrum. Today, for Light People, we feature a researcher who is committed to exploring different spectral bands of light ranging from deep ultraviolet to terahertz waves and working on quantum semiconductor technology, Prof. Manijeh Razeghi of the Northwestern University in the United States. Known for her quick thinking and witty remarks, Prof. Razeghi is passionate about life and always kind to others. As a scientist, she does not limit her research to a single focus, instead, she works on the entire process from material selection, device design, processing, and manufacturing, all the way to product application. She has a strong passion for education, a commitment unwavered by fame or fortune. For her students, she is both a reliable source of knowledge and a motherly figure with a caring heart. She firmly believes that all things in nature can give her energy and inspiration. In science, she is a true “pioneer” in research and a “miner” of scientific discoveries. She advises young scientists to enjoy and love what they do, and turn their research into their hobby. As a female scientist, she calls on all women to realize their true value and potential. Next, let’s hear from Professor Manijeh Razeghi, a true star who radiates energy and light.
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