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Pubblicazioni recenti - cardiac stem
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F-53B and PFOS treatments skew human embryonic stem cell in vitro cardiac differentiation towards epicardial cells by partly disrupting the WNT signaling pathway.
Environ Pollut2020 Feb;261():114153. doi: S0269-7491(19)34986-3.
Yang Renjun, Liu Shuyu, Liang Xiaoxing, Yin Nuoya, Ruan Ting, Jiang Linshu, Faiola Francesco,
Abstract
F-53B and PFOS are two per- and polyfluoroalkyl substances (PFASs) widely utilized in the metal plating industry as mist suppressants. Recent epidemiological studies have linked PFASs to cardiovascular diseases and alterations in heart geometry. However, we still have limited understanding of the effects of F-53B and PFOS on the developing heart. In this study, we employed a human embryonic stem cell (hESC)-based cardiac differentiation system and whole transcriptomics analyses to evaluate the potential developmental cardiac toxicity of F-53B and PFOS. We utilized F-53B and PFOS concentrations of 0.1-60 ?M, covering the levels detected in human blood samples. We demonstrated that both F-53B and PFOS inhibited cardiac differentiation and promoted epicardial specification via upregulation of the WNT signaling pathway. Most importantly, the effects of F-53B were more robust than those of PFOS. This was because F-53B treatment disrupted the expression of more genes and led to lower cardiac differentiation efficiency. These findings imply that F-53B may not be a safe replacement for PFOS.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Improving quality of life in hematopoietic stem cell transplant survivors through a positive psychology intervention.
Biol Blood Marrow Transplant2020 Feb;():. doi: S1083-8791(20)30098-7.
Amonoo Hermioni L, Kurukulasuriya Chareeni, Chilson Kate, Onstad Lynn, Huffman Jeff C, Lee Stephanie J,
Abstract
BACKGROUND:
Despite advances in transplantation medicine, psychological distress, quality of life and functional deficits continue to compromise survivorship after hematopoietic stem cell transplantation (HSCT). With increasing numbers of HSCT survivors, supportive oncology interventions that target health-related outcomes in HSCT survivorship are needed. Hence, we aimed to test the feasibility and acceptability of a group format phone-delivered positive psychology (PP) intervention in HSCT survivors.
METHODS:
This is a one-arm pilot study design that adapted and tested an individual PP intervention used in cardiac disease to a phone-delivered group-based program for HSCT survivors who were 0.4 to 39 years post-transplant. All participants received the 8-session weekly PP intervention. We assessed feasibility by the enrollment and intervention completion rates. We examined acceptability on a 10-point Likert scale of ease and utility. Unstructured qualitative interviews were used to obtain participant feedback on the intervention for future application in a larger trial. Self-reported assessments on psychological, functional, and quality of life outcomes were administered at baseline and at follow-up (the end of the intervention).
RESULTS:
Of 64 eligible participants, 29 (45%) enrolled in the study. For the main aim of intervention feasibility and acceptability, participants completed 96% of all PP sessions and participants rated the ease (7.6 [SD 1.7]) and utility (8.1 [SD 1.1]) of sessions highly. Of the self-reported assessments obtained, the PP intervention resulted in improvements in the resilience scale (mean difference 2.4 [SD 5.4], p=0.03). From unstructured qualitative interviews, participants reported the PP exercises and intervention helped them to focus on positive emotions and the group format fostered a sense of community and social support.
CONCLUSION:
An 8-week phone-delivered group format PP intervention is feasible and acceptable in HSCT survivors. The piloted intervention could be tested with minor modifications in a randomized study to definitively examine the impact of the group format PP intervention on health-related outcomes.
Copyright © 2020. Published by Elsevier Inc.
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Cardiac adverse events during stem cell transplantation for hematological malignancies: A single centre experience.
Transfus Apher Sci2020 Feb;():102653. doi: S1473-0502(19)30217-4.
Aladag Elifcan, Demiroglu Haluk, Buyukasik Yahya, Karakulak Ugur N, Tekin Fatma, Aksu Salih, Goker Hakan,
Abstract
Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment option for many hematological malignancies. Several adverse effects can be seen in HSCT due to the infusion and damage caused by the conditioning regimens. Cardiovascular adverse effects are relatively common during HSCT, and they have the potential to cause devastating complications. The aim of present study was to evaluate the transplantation-related cardiac adverse effects and determine the risk factors in patients undergoing HSCT at our institution. A retrospective analysis has been performed in 662 patients who was treated at Hacettepe University Stem Cell Transplantation Unit. Amongst the 622 patients, 318 (51.1 %) underwent autologous and 304 (48.9 %) underwent allogeneic HSCT. The frequency of the cardiac adverse effects was found to be 10.8 % in all the study population. The most common adverse effect was tachyarrhythmia, constituting 7.9 % of all population. These adverse effects were mostly occurred in lymphoma patients (14 %). Nineteen (3.0 %) of all patients developed atrial fibrillation mostly on the 4th day (range of 1-9 days) after transplantation. Life-threatening events are extremely rare. These adverse effects appear to be related to the type of transplantation rather than the underlying disease. Therefore, close follow-up of patients is important during the peri-transplantation period.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Role of Apelin/APJ axis in cancer development and progression.
Adv Med Sci2020 Feb;65(1):202-213. doi: S1896-1126(20)30007-9.
Masoumi Javad, Jafarzadeh Abdollah, Khorramdelazad Hossein, Abbasloui Morteza, Abdolalizadeh Jalal, Jamali Najmeh,
Abstract
Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues. The apelin receptor, called angiotensin-like-receptor 1 (APJ), is also expressed in the brain, spleen, placenta, heart, liver, intestine, prostate, thymus, testis, ovary, lungs, kidneys, stomach, and adipose tissue. The apelin/APJ axis is involved in a number of physiological and pathological processes. The apelin expression is increased in various kinds of cancer and the apelin/APJ axis plays a key role in the development of tumors through enhancing angiogenesis, metastasis, cell proliferation and also through the development of cancer stem cells and drug resistance. The apelin also stops the apoptosis of cancer cells. The apelin/APJ axis was considered in this review as an attractive therapeutic target for cancer treatment.
Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.
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Human Amnion Membrane Proteins Prevent Doxorubicin-Induced Oxidative Stress Injury and Apoptosis in Rat H9c2 Cardiomyocytes.
Cardiovasc Toxicol2020 Feb;():. doi: 10.1007/s12012-020-09564-8.
Faridvand Yousef, Haddadi Parinaz, Vahedian Vahid, Nozari Samira, Nejabati Hamid Reza, Pezeshkian Masoud, Afrasiabi Abbas, Safaie Nasser, Jodati Ahmadreza, Nouri Mohammad,
Abstract
Doxorubicin (DOX) is widely used as an effective chemotherapy agent in cancer treatment. Cardiac toxicity in cancer treatment with DOX demand urgent attention and no effective treatment has been established for DOX-induced cardiomyopathy. It has been well documented that human amniotic membrane proteins (AMPs), extracted from amnion membrane (AM), have antioxidant, anti-apoptotic, and cytoprotective properties. Therefore, in this study, we aimed to investigate the protective effects of AMPs against cardiotoxicity induced by DOX in cultured rat cardiomyocyte cells (H9c2). DOX-induced cell injury was evaluated using multi-parametric assay including thiazolyl blue tetrazolium bromide (MTT), the release of lactic dehydrogenase (LDH), intracellular Ca2+?, reactive oxygen species (ROS) levels, cellular antioxidant status, mitochondrial membrane potential (??m), malondialdehyde (MDA), and NF-?B p65 DNA-binding activity. Moreover, expression profiling of apoptosis-related genes (P53, Bcl-2, and Bax) and Annexin V by flow cytometry were used for cell apoptosis detection. It was shown that AMPs pretreatment inhibited the cell toxicity induced by DOX. AMPs effectively attenuated the increased levels of LDH, Ca2+?, ROS, and MDA and also simultaneously elevated the ??m and antioxidant status such as superoxide dismutase (SOD) and Catalase (CAT) in pretreated H9c2 cardiomyocytes. Besides, the activity of NF-kB p65 was reduced and the p53 and Bax protein levels were inhibited in these myocardial cells subjected to DOX. These findings provide the first evidence that AMPs potently suppressed DOX-induced toxicity in cardiomyocytes through inhibition of oxidative stress and apoptosis. Thus, AMPs can be a potential therapeutic agent against DOX cardiotoxicity.
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Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis.
Nucleic Acids Res2020 Feb;():. doi: gkaa098.
Li Ying, Liao Ziwei, Luo Huacheng, Benyoucef Aissa, Kang Yuanyuan, Lai Qian, Dovat Sinisa, Miller Barbara, Chepelev Iouri, Li Yangqiu, Zhao Keji, Brand Marjorie, Huang Suming,
Abstract
Aberrant activation of the TAL1 is associated with up to 60% of T-ALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemia-prone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts.
Stem Cell Res Ther2020 Feb;11(1):73. doi: 10.1186/s13287-020-01602-0.
Guan Xumin, Xu Wanzi, Zhang He, Wang Qian, Yu Jiuyang, Zhang Ruyi, Chen Yamin, Xia Yunlong, Wang Jiaxian, Wang Dongjin,
Abstract
BACKGROUND:
Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results.
OBJECTIVES:
The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model.
METHODS:
Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1?×?10 human iPSC-CMs 10?days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant? CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas.
RESULTS:
Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4?weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group.
CONCLUSIONS:
Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4?weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.
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Silk-reinforced Collagen Hydrogels with Raised Multiscale Stiffness for Mesenchymal Cells 3D Culture.
Tissue Eng Part A2020 Feb;():. doi: 10.1089/ten.TEA.2019.0199.
Sanz-Fraile Hector, Amorós Susana, Mendizabal Irene Isabel, Gálvez-Montón Carolina, Prat-Vidal Cristina, Bayés-Genís Antoni, Navajas Daniel, Farre Ramon, Otero Jorge,
Abstract
Type I collagen hydrogels are of high interest in tissue engineering. With the evolution of 3D bioprinting technologies, a high number of collagen-based scaffolds have been reported for the development of 3D cell cultures. A recent proposal was to mix collagen with silk fibroin derived from Bombyx Mori silkworm. Nevertheless, due to the difficulties in the preparation and the characteristics of the protein, several problems like phase separation and collagen denaturation appears during the procedure. Therefore, the common solution is to diminish the concentration of collagen although in that way the most biologically relevant component is reduced. In the present work, we present a new, simple and effective method to develop a collagen-silk hybrid hydrogel with high collagen concentration and with increased stiffness approaching that of natural tissues, which could be of high interest for the development of cardiac patches for myocardial regeneration and for preconditioning of mesenchymal stem cells to improve their therapeutic potential. Sericin in the silk was preserved by using a physical solubilizing procedure which results in a preserved fibrous structure of type I collagen, as shown by ultrastructural imaging. The macro- and micromechanical properties of the hybrid hydrogels measured by tensile stretch and Atomic Force Microscopy respectively, showed a more than two-fold stiffening as compared with collagen-only hydrogels. Rheological measurements showed improved printability properties for the developed biomaterial. The suitability of the hydrogels for 3D cell culture was assessed by 3D bioprinting bone marrow-derived mesenchymal stem cells cultured within the scaffolds. The result was a biomaterial with improved printability characteristics that better resembled the mechanical properties of natural soft tissues while preserving biocompatibility owing to the high concentration of collagen.
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ERS International Congress, Madrid, 2019: highlights from the Airway Diseases, Asthma and COPD Assembly.
ERJ Open Res2020 Jan;6(1):. doi: 00341-2019.
Lahousse Lies, Bahmer Thomas, Cuevas-Ocańa Sara, Flajolet Pauline, Mathioudakis Alexander G, McDonnell Melissa, Uller Lena, Schleich Florence, Dortas Junior Sergio, Idzko Marco, Singh Dave, Ricciardolo Fabio L M, Adcock Ian M, Usmani Omar, Spanevello Antonio, Bonvini Sara J,
Abstract
The European Respiratory Society (ERS) International Congress 2019 in Madrid, Spain, was a platform for scientific discussion of the highest quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses some of the high-quality research studies presented at that Congress, with a focus on airway diseases, including asthma, COPD, small airways, bronchiectasis and cough, presented through the Airway Diseases, Asthma and COPD Assembly (Assembly 5) of the ERS. The authors establish the key take-home messages of these studies, compare their findings and place them into context of current understanding.
Copyright ©ERS 2020.
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Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, lead to noncompaction cardiomyopathy in mice.
Biochem Biophys Res Commun2020 Feb;():. doi: S0006-291X(20)30311-9.
Kosugi Mayuko, Otani Mai, Kikkawa Yurika, Itakura Yoko, Sakai Kohei, Ito Toshiaki, Toyoda Masashi, Sekita Yoichi, Kimura Tohru,
Abstract
Mammalian X and Y chromosomes evolved from a pair of autosomes. Although most ancestral genes have been lost from the Y chromosome, a small number of ancestral X-Y gene pairs are still present on the sex chromosomes. The KDM5C and KDM5D genes, which encode H3K4 histone demethylases, are a surviving ancestral gene pair located on the X and Y chromosomes, respectively. Mutations in KDM5C cause X-linked intellectual disability in human males, suggesting functional divergence between KDM5C and KDM5D in the nervous system. In this study, to explore the functional conservation and divergence between these two genes in other organs, we generated female mice lacking Kdm5c (homozygous X X females) and male mice lacking both Kdm5c and Kdm5d (compound hemizygous X Y males). Both X X females and X Y males showed lower body weights and postnatal lethality. Histological examination of the hearts showed prominent trabecular extension and a thin layer of compacted myocardium in the left and right ventricles, indicating noncompaction cardiomyopathy. However, hemizygous males lacking either Kdm5c or Kdm5d showed no signs of noncompaction cardiomyopathy. These results clearly demonstrate that the function of Kdm5c and Kdm5d in heart development is conserved.
Copyright © 2020 Elsevier Inc. All rights reserved.
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The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination.
Antiviral Res2020 Feb;():104732. doi: S0166-3542(19)30506-6.
Griffiths Paul,
Abstract
Active infection with cytomegalovirus (CMV) occurs in patients who are immunocompromised and may produce the high viral loads required to cause end-organ disease. Such patients have complex medical histories and many experienced physicians have speculated that CMV may, additionally, contribute to adverse clinical outcomes. In 1989, Dr Bob Rubin coined the term "indirect effects" to describe this potential relationship between virus and patient. Examples include accelerated atherosclerosis in patients after heart transplant or with underlying HIV infection, the number of days patients require ventilation after admission to intensive care units, the development of immunosenescence in the elderly and mortality in many groups of patients, including the general population. It is difficult to distinguish between CMV acting as causal contributor to such diverse pathology or simply having a benign bystander effect. However, recruitment of patients into placebo-controlled randomised trials of antiviral drugs with activity against CMV offers such a potential. This article describes the studies that have been conducted to date and emphasises that mortality after stem cell transplant (not attributed to CMV end-organ disease) has recently become the first proven indirect effect of CMV now that letermovir has significantly reduced non-relapse deaths. The implications for CMV vaccines are then discussed. Vaccines are already predicted to be highly cost-effective if they can reduce CMV end-organ disease. Health planners should now consider that cost effectiveness is likely to be enhanced further through reduction of the indirect effects of CMV. A prototype scheme for assessing this possibility is provided in order to stimulate discussion within the field. This article forms part of an online symposium on the prevention and therapy of DNA virus infections, dedicated to the memory of Mark Prichard.
Copyright © 2020 Elsevier B.V. All rights reserved.
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Stem cells and the heart-the road ahead.
Science2020 Feb;367(6480):854-855. doi: 10.1126/science.aaz3650.
Murry Charles E, MacLellan W Robb,
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A cell atlas of human thymic development defines T cell repertoire formation.
Science2020 Feb;367(6480):. doi: eaay3224.
Park Jong-Eun, Botting Rachel A, Domínguez Conde Cecilia, Popescu Dorin-Mirel, Lavaert Marieke, Kunz Daniel J, Goh Issac, Stephenson Emily, Ragazzini Roberta, Tuck Elizabeth, Wilbrey-Clark Anna, Roberts Kenny, Kedlian Veronika R, Ferdinand John R, He Xiaoling, Webb Simone, Maunder Daniel, Vandamme Niels, Mahbubani Krishnaa T, Polanski Krzysztof, Mamanova Lira, Bolt Liam, Crossland David, de Rita Fabrizio, Fuller Andrew, Filby Andrew, Reynolds Gary, Dixon David, Saeb-Parsy Kourosh, Lisgo Steven, Henderson Deborah, Vento-Tormo Roser, Bayraktar Omer A, Barker Roger A, Meyer Kerstin B, Saeys Yvan, Bonfanti Paola, Behjati Sam, Clatworthy Menna R, Taghon Tom, Haniffa Muzlifah, Teichmann Sarah A,
Abstract
The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8?? T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials.
ESMO Open2020 Feb;5(1):. doi: e000659.
Eiger Daniel, Franzoi Maria Alice, Pondé Noam, Brandăo Mariana, de Angelis Claudia, Schmitt Nogueira Melanie, de Hemptinne Quentin, de Azambuja Evandro,
Abstract
BACKGROUND:
Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question.
MATERIALS AND METHODS:
A meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting.
RESULTS:
Clinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11?250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias.
CONCLUSIONS:
Compared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.
© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.
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N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through A ?-Catenin Dependent Manner.
Circ Res2020 Feb;():. doi: 10.1161/CIRCRESAHA.119.315806.
Yan Wenjun, Lin Chen, Guo Yongzhen, Chen Youhu, Du Yunhui, Lau Wayne Bond, Xia Yunlong, Zhang Fuyang, Su Renzhi, Gao Erhe, Wang Yajing, Li Congye, Liu Rui, Ma Xin-Liang, Tao Ling,
Abstract
Mesenchymal stromal cells (MSC)-based therapy is promising against ischemic heart failure (IHF). However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. The current study investigates whether and how N-cadherin may regulate MSC retention and cardioprotective capability against IHF. Adult mice-derived adipose tissue-derived MSC (ADSC) were transfected with adenovirus harboring N-cadherin (ADSC-Ncad), T-cadherin (ADSC-Tcad), or control adenovirus (ADSC-con). CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion (MI/R). ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was employed to determine the molecular mechanisms. Compared to ADSC-con, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC-Ncad significantly preserved capillary density and increased cardiomyocyte proliferation, and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC-Ncad (but not ADSC-Tcad) significantly increased LVEF and reduced fibrosis in both MI and MI/R mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP-10/13 and/or HGF upregulation is responsible for N-cadherin's effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/?-catenin complex formation and active ?-catenin levels in the nucleus. ?-catenin knockdown abolished N-cadherin overexpression induced MMP-10, MMP-13, and HGF expression, and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin. We demonstrate for the first time that N-cadherin overexpression enhances MSC protective effects against IHF via ?-catenin mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.
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Mesenchymal Stem Cells Promote the Resolution of Cardiac Inflammation After Ischemia Reperfusion Via Enhancing Efferocytosis of Neutrophils.
J Am Heart Assoc2020 Mar;9(5):e014397. doi: 10.1161/JAHA.119.014397.
Zhang Zeyu, Tian Hongzhen, Yang Chen, Liu Jixuan, Zhang Huawei, Wang Jinda, Hu Shunying, Sun Zhijun, He Kunlun, Chen Guanghui,
Abstract
Background Neutrophils play a major role in inflammation after myocardial ischemia-reperfusion (I/R) injury. The effects of mesenchymal stem cells (MSCs) on neutrophils in I/R are complex and not fully understood. This study was designed to investigate the effects and mechanism of MSCs on alleviating myocardial I/R injury in rats. Methods and Results MSCs induced M2 macrophages polarization in vitro and enhanced macrophage efferocytosis of apoptotic neutrophils, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. Rats myocardial I/R were induced by transient ligation of left anterior descending coronary. Adipose-derived MSCs or vehicle were infused at initiation (immediate after reperfusion) or peak of inflammation (24 hours after I/R). Hematoxylin and eosin, 2,3,5-triphenyltetrazolium chloride/Evans Blue staining and immunofluorescence staining were applied within 72 hours after cell infusion. Cardiac function was assessed by echocardiography and left cardiac catheterization analysis at 28 days post-operation. MSCs infused immediately and 24 hours later both markedly ameliorated myocardial I/R injury, and immediate infusion had more significant outcome. These improvements were associated with neutrophils infiltration, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. When infused immediately, MSCs did not significantly change neutrophil number at 24 hours but CD11b expression was significantly higher. When infused at 24 hours, MSCs markedly decreased neutrophil number by enhanced M2 macrophage infiltration and macrophage efferocytosis of neutrophils within 72 hours. Conclusions Efferocytosis is pivotal to relieve neutrophil-mediated I/R injury and initial the immune response for healing. MSCs infusion improves cardiac function in rats after myocardial I/R via the possible mechanism of enhancing M2 macrophages-induced efferocytosis of apoptotic neutrophils.
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Separation of HCM and LQT Cardiac Diseases with Machine Learning of Ca2+ Transient Profiles.
Methods Inf Med2020 Feb;():. doi: 10.1055/s-0040-1701484.
Joutsijoki Henry, Penttinen Kirsi, Juhola Martti, Aalto-Setälä Katriina,
Abstract
BACKGROUND:
?Modeling human cardiac diseases with induced pluripotent stem cells not only enables to study disease pathophysiology and develop therapies but also, as we have previously showed, it can offer a tool for disease diagnostics. We previously observed that a few genetic cardiac diseases can be separated from each other and healthy controls by applying machine learning to Ca transient signals measured from iPSC-derived cardiomyocytes (CMs).
OBJECTIVES:
?For the current research, 419 hypertrophic cardiomyopathy (HCM) transient signals and 228 long QT syndrome (LQTS) transient signals were measured. HCM signals included data recorded from iPSC-CMs carrying either ?-tropomyosin, i.e., TPM1 (HCMT) or MYBPC3 or myosin-binding protein C (HCMM) mutation and LQTS signals included data recorded from iPSC-CMs carrying potassium voltage-gated channel subfamily Q member 1 (KCNQ1) mutation (long QT syndrome 1 [LQT1]) or KCNH2 mutation (long QT syndrome 2 [LQT2]). The main objective was to study whether and how effectively HCMM and HCMT can be separated from each other as well as LQT1 from LQT2.
METHODS:
?After preprocessing those Ca signals where we computed peak waveforms we then classified the two mutations of both disease pairs by using several different machine learning methods.
RESULTS:
?We obtained excellent classification accuracies of 89% for HCM and even 100% for LQT at their best.
CONCLUSION:
?The results indicate that the methods applied would be efficient for the identification of these genetic cardiac diseases.
Georg Thieme Verlag KG Stuttgart · New York.
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Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity.
J Cardiovasc Transl Res2020 Feb;():. doi: 10.1007/s12265-020-09962-x.
Pinheiro Emily A, Magdy Tarek, Burridge Paul W,
Abstract
Chemotherapy-induced cardiovascular toxicity (CICT) is a well-established risk for cancer survivors and causes diseases such as heart failure, arrhythmia, vascular dysfunction, and atherosclerosis. As our knowledge of the precise cardiovascular risks of each chemotherapy agent has improved, it has become clear that genomics is one of the most influential predictors of which patients will experience cardiovascular toxicity. Most recently, GWAS-led, top-down approaches have identified novel genetic variants and their related genes that are statistically related to CICT. Importantly, the advent of human-induced pluripotent stem cell (hiPSC) models provides a system to experimentally test the effect of these genomic findings in vitro, query the underlying mechanisms, and develop novel strategies to mitigate the cardiovascular toxicity liabilities due to these mechanisms. Here we review the cardiovascular toxicities of chemotherapy drugs, discuss how these can be modeled in vitro, and suggest how these models can be used to validate genetic variants that predispose patients to these effects.
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Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.
Circulation2020 Feb;():. doi: 10.1161/CIRCULATIONAHA.119.043067.
Magadum Ajit, Singh Neha, Kurian Ann Anu, Munir Irsa, Mehmood Talha, Brown Kemar, Sharkar Mohammad Tofael Kabir, Chepurko Elena, Sassi Yassine, Oh Jae Gyun, Lee Philyoung, Santos Celio X C, Gaziel-Sovran Avital, Zhang Guoan, Cai Chen-Leng, Kho Changwon, Mayr Manuel, Shah Ajay M, Hajjar Roger J, Zangi Lior,
Abstract
The adult mammalian heart has limited regenerative capacity, mostly due to postnatal cardiomyocyte (CM) cell cycle arrest. In the last two decades, numerous studies have explored CM cell cycle regulatory mechanisms to enhance myocardial regeneration post myocardial infarction (MI). Pyruvate kinase muscle isozyme 2 (Pkm2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in CM proliferation, heart development and cardiac regeneration is unknown. We investigated the effect of Pkm2 in CM through models of loss (CM-specific Pkm2 deletion during cardiac development) or gain using CM-specific Pkm2 modified mRNA (Pkm2 modRNA) to evaluate Pkm2 function and regenerative affects post-acute or -chronic MI in mice. Here, we identify Pkm2 as an important regulator of the CM cell cycle. We show that Pkm2 is expressed in CMs during development and immediately after birth but not during adulthood. Loss of function studies show that CM-specific Pkm2 deletion during cardiac development resulted in significantly reduced CM cell cycle, CM numbers and myocardial size. In addition, using Pkm2 modRNA, our novel CM-targeted strategy, following acute or chronic MI resulted in increased CM cell division, enhanced cardiac function and improved long-term survival. We mechanistically show that Pkm2 regulates the CM cell cycle and reduces oxidative stress damage through anabolic pathways and ?-catenin. We demonstrate that Pkm2 is an important intrinsic regulator of the CM cell cycle and oxidative stress and highlight its therapeutic potential using CMSPkm2 modRNA as a gene delivery platform.
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Nox2+ Myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1.
Cardiovasc Res2020 Feb;():. doi: cvaa042.
Molitor Michael, Rudi Wolf-Stephan, Garlapati Venkata, Finger Stefanie, Schüler Rebecca, Kossmann Sabine, Lagrange Jeremy, Nguyen Thanh Son, Wild Johannes, Knopp Tanja, Karbach Susanne H, Knorr Maike, Ruf Wolfram, Münzel Thomas, Wenzel Philip,
Abstract
AIMS:
Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI.
METHODS AND RESULTS:
HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ hematopoietic stem cells and Sca-1-c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G-Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 d starting 28d after MI. While the cardiac phenotype remained unaltered until 38d post MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: Telmisartan (20?mg/kg/d, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid ROS production, attenuated endothelial leukocyte rolling and vascular accumulation of CD11b+Ly6G-Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells.
CONCLUSION:
Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: journals.permissions@oup.com.
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