Pubblicazioni recenti - cardiac stem

• Integrated Ca2+ flux and AFM force analysis in human iPSC-derived cardiomyocytes.
  Biol Chem

  2020 Oct;():. doi: 10.1515/hsz-2020-0212.
  
  Malkovskiy Andrey V, Ignatyeva Nadezda, Dai Yuanyuan, Hasenfuss Gerd, Rajadas Jayakumar, Ebert Antje,
  
  Abstract
  
  We developed a new approach for combined analysis of calcium (Ca2+) handling and beating forces in contractile cardiomyocytes. We employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from dilated cardiomyopathy (DCM) patients carrying an inherited mutation in the sarcomeric protein troponin T (TnT), and isogenic TnT-KO iPSC-CMs generated via CRISPR/Cas9 gene editing. In these cells, Ca2+ handling as well as beating forces and -rates using single-cell atomic force microscopy (AFM) were assessed. We report impaired Ca2+ handling and reduced contractile force in DCM iPSC-CMs compared to healthy WT controls. TnT-KO iPSC-CMs display no contractile force or Ca2+ transients but generate Ca2+ sparks. We apply our analysis strategy to Ca2+ traces and AFM deflection recordings to reveal maximum rising rate, decay time, and duration of contraction with a multi-step background correction. Our method provides adaptive computing of signal peaks for different Ca2+ flux or force levels in iPSC-CMs, as well as analysis of Ca2+ sparks. Moreover, we report long-term measurements of contractile force dynamics on human iPSC-CMs. This approach enables deeper and more accurate profiling of disease-specific differences in cardiomyocyte contraction profiles using patient-derived iPSC-CMs.
  
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• Somatic Mutations in and Severe Adult-Onset Autoinflammatory Disease.
  N Engl J Med

  2020 Oct;():. doi: 10.1056/NEJMoa2026834.
  
  Beck David B, Ferrada Marcela A, Sikora Keith A, Ombrello Amanda K, Collins Jason C, Pei Wuhong, Balanda Nicholas, Ross Daron L, Ospina Cardona Daniela, Wu Zhijie, Patel Bhavisha, Manthiram Kalpana, Groarke Emma M, Gutierrez-Rodrigues Fernanda, Hoffmann Patrycja, Rosenzweig Sofia, Nakabo Shuichiro, Dillon Laura W, Hourigan Christopher S, Tsai Wanxia L, Gupta Sarthak, Carmona-Rivera Carmelo, Asmar Anthony J, Xu Lisha, Oda Hirotsugu, Goodspeed Wendy, Barron Karyl S, Nehrebecky Michele, Jones Anne, Laird Ryan S, Deuitch Natalie, Rowczenio Dorota, Rominger Emily, Wells Kristina V, Lee Chyi-Chia R, Wang Weixin, Trick Megan, Mullikin James, Wigerblad Gustaf, Brooks Stephen, Dell'Orso Stefania, Deng Zuoming, Chae Jae J, Dulau-Florea Alina, Malicdan May C V, Novacic Danica, Colbert Robert A, Kaplan Mariana J, Gadina Massimo, Savic Sinisa, Lachmann Helen J, Abu-Asab Mones, Solomon Benjamin D, Retterer Kyle, Gahl William A, Burgess Shawn M, Aksentijevich Ivona, Young Neal S, Calvo Katherine R, Werner Achim, Kastner Daniel L, Grayson Peter C,
  
  Abstract
  
  BACKGROUND:
  Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
  
  METHODS:
  We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.
  
  RESULTS:
  We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
  
  CONCLUSIONS:
  Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
  
  Copyright © 2020 Massachusetts Medical Society.
  
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• Hyaluronate supports hESC-cardiomyocyte cell therapy for cardiac regeneration after acute myocardial infarction.
  Cell Prolif

  2020 Oct;():e12942. doi: 10.1111/cpr.12942.
  
  Tan Yuanqing, Wang Lei, Chen Gang, Liu Wenjing, Li Zhongwen, Wang Yukai, Wang Liu, Li Wei, Wu Jun, Hao Jie,
  
  Abstract
  
  INTRODUCTION:
  Enormous progress has been made in cardiac regeneration using human embryonic stem cell-derived cardiomyocyte (hESC-CM) grafts in pre-clinical trials. However, the rate of cell survival has remained very low due to anoikis after transplantation into the heart as single cells. Numerous solutions have been proposed to improve cell survival, and one of these strategies is to co-transplant biocompatible materials or hydrogels with the hESC-CMs.
  
  METHODS:
  In our study, we screened various combinations of biomaterials that could promote anoikis resistance and improve hESC-CM survival upon co-transplantation and promote cardiac functional recovery. We injected different combinations of Matrigel, alginate and hyaluronate with hESC-CM suspensions into the myocardium of rat models with myocardial infarction (MI).
  
  RESULTS:
  Our results showed that the group treated with a combination of hyaluronate and hESC-CMs had the lowest arrhythmia rates when stimulated with programmed electrical stimulation. While all three combinations of hydrogel-hESC-CM treatments improved rat cardiac function compared with the saline control group, the combination with hyaluronate most significantly reduced pathological changes from left ventricular remodelling and improved both left ventricular function and left ventricular ejection fraction by 28 days post-infarction.
  
  CONCLUSION:
  Hence, we concluded that hyaluronate-hESC-CM is a superior combination therapy for promoting cardiac regeneration after myocardial infarction.
  
  © 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
  
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• Cardiac fibroblast paracrine factors modulate mouse embryonic stem cells.
  Sheng Li Xue Bao

  2020 Oct;72(5):651-659.
  
  Shen Dan-Ya, Chen Zong-Hai, Zhao Ya-Nan, Zhou Jian-Xia, Guan Xiu-Wen, Liang Hua-Min,
  
  Abstract
  
  The study aims to investigate the effects of cardiac fibroblast (CF) paracrine factors on murine embryonic stem cells (ESCs). Conditioned mediums from either neonatal cardiac fibroblasts (ConM-NCF) or adult cardiac fibroblasts (ConM-ACF) were diluted by 1:50 and 1:5, respectively, to investigate whether these conditioned mediums impact murine ESCs distinctly with RT-real time PCR techniques, cell proliferation essay, ELISA and by counting percentage of beating embryoid bodies (EBs) during ESCs differentiation. The data showed that the paracrine ability of CFs changed dramatically during development, in which interleukin 6 (IL6) increased with maturation. ConM-NCF 1:50 and ConM-NCF 1:5 had opposite effects on the pluripotent markers, although they both reduced mouse ESC proliferation. ConM-ACF 1:50 promoted ESCs pluripotent markers and proliferation, while ConM-ACF 1:5 exerted negative effects. All CF-derived conditioned mediums inhibited cardiac differentiation, but with distinguishable features: ConM-NCF 1:50 slightly decreased the early cardiac differentiation without altering the maturation tendency or cardiac specific markers in EBs at differentiation of day 17; ConM-ACF 1:50 had more significant inhibitory effects on early cardiac differentiation than ConM-NCF 1:50 and impeded cardiac maturation with upregulation of cardiac specific markers. In addition, IL6 neutralization antibody attenuated positive effect of ConM-ACF 1:50 on ESCs proliferation, but had no effects on ConM-NCF 1:50. Long-term IL6 neutralization reduced the percentage of beating EBs at early developmental stage, but did not alter the late cardiac differentiation. Taken together, both the quality and quantity of factors and cytokines secreted by CFs are critical for the ESC fate. IL6 could be a favorable cytokine for ESC pluripotency and the early cardiac differentiation.
  
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• The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.
  Nat Cell Biol

  2020 Oct;():. doi: 10.1038/s41556-020-00595-5.
  
  Zhang Yaohua, Li Yajuan, Hu Qingsong, Xi Yutao, Xing Zhen, Zhang Zhao, Huang Lisa, Wu Jianbo, Liang Ke, Nguyen Tina K, Egranov Sergey D, Sun Chengcao, Zhao Zilong, Hawke David H, Li Jin, Sun Deqiang, Kim Jean J, Zhang Ping, Cheng Jie, Farida Abid, Hung Mien-Chie, Han Leng, Darabi Radbod, Lin Chunru, Yang Liuqing,
  
  Abstract
  
  Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys?3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR-H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR-H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.
  
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• Role of Stem Cell Derived Microvesicles in Cardiovascular Disease.
  J Cardiovasc Pharmacol

  2020 Oct;():. doi: 10.1097/FJC.0000000000000920.
  
  Kraus Lindsay, Mohsin Sadia,
  
  Abstract
  
  The role of stem cells in augmenting reparative processes in the heart after ischemic injury has been successfully demonstrated in small and large animal models. However, the outcomes of cell therapy in clinical trials have been somewhat variable, with overall effects of autologous stem cell therapies demonstrating a modest improvement in cardiac structure and function. How stem cells repair the heart after cardiac injury is still not well understood. Most recent studies suggest that adult derived stem cells act primarily through paracrine signaling to exert beneficial effects, including modulation of immune response, stimulation of new blood vessel formation or by inducing mature myocytes to transiently reenter the cell cycle, rather than robust direct differentiation of the transplanted cells into myocytes. Additionally, data from multiple labs confirmed clearance of stem cells themselves within a few days still leading to functional benefits further confirming the role of paracrine signaling in augmenting cardiac reparative processes rather than direct differentiation of cells. These findings rapidly evolved the field of extracellular vesicles specifically microvesicles as they are active hubs of autocrine, paracrine and endocrine signaling targeting different biological processes. The beneficial effects seen after stem cell transplantation could be linked to the cardioprotective factors packaged in the microvesicles secreted from stem cells. Therefore, stem cell microvesicles provide a new avenue for the treatment of cardiovascular disease through a multitude of mechanisms including cellular communication within the stem cell niches, delivery of genetic information, regulation of the immune system in the heart, and stimulation of angiogenesis which will be discussed in this review.
  
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• Isolation of Cardiomyocytes from Fixed Hearts for Immunocytochemistry and Ploidy Analysis.
  J Vis Exp

  2020 Oct;(164):. doi: 10.3791/60938.
  
  Yücel Do?acan, Solinsky Jacob, van Berlo Jop H,
  
  Abstract
  
  The adult mammalian heart is composed of various cell types including cardiomyocytes, endothelial cells and fibroblasts. Since it is difficult to reliably identify nuclei of cardiomyocytes on histological sections, many groups rely on isolating viable cardiomyocytes prior to fixation to perform immunostaining. However, these live cardiomyocyte isolation techniques require optimization to maximize the yield, viability and quality of the samples, with inherent fluctuations from sample to sample despite maximum optimization. Here, we report a reproducible protocol, involving fixation prior to enzymatic digestion of the heart, which leads to maximum yield while preserving the in vivo morphology of individual cardiomyocytes. We further developed an automated analysis platform to determine the number of nuclei and DNA content per nucleus for individual cardiomyocytes. After exposing the chest cavity, the heart was arrested in diastole by perfusion with 60 mM KCl in PBS. Next, the heart was fixed in 4% paraformaldehyde (PFA) solution, and then digested with 60 mg/mL collagenase solution. After digestions, cells were singularized by trituration, and the cardiomyocyte fraction was enriched via differential centrifugation. Isolated cardiomyocytes were stained for Troponin T and ?-actinin to assess purity of the obtained population. Furthermore, we developed an image analysis platform to determine cardiomyocyte nucleation and ploidy status following DAPI staining. Image based ploidy assessments led to consistent and reproducible results. Thus, with this protocol, it is possible to preserve native morphology of individual cardiomyocytes to allow immunocytochemistry and DNA content analysis while achieving maximum yield.
  
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• Prognostic implication of SOX2 expression in small intestinal adenocarcinoma.
  Virchows Arch

  2020 Oct;():. doi: 10.1007/s00428-020-02946-x.
  
  Kim Jeong Won, Chung Joon-Yong, Ylaya Kris, Park Yoonho, Jun Sun-Young, Hong Seung-Mo, Hewitt Stephen M,
  
  Abstract
  
  The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2-) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRAS) (11.1 months) had significantly shorter overall survival than those with SOX2-/KRAS (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.
  
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• Trends and Limitations in the Assessment of the Contractile Properties of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes From Patients With Dilated Cardiomyopathy.
  Front Cardiovasc Med

  2020 ;7():154. doi: 10.3389/fcvm.2020.00154.
  
  Ito Masamichi, Nomura Seitaro, Morita Hiroyuki, Komuro Issei,
  
  Abstract
  
  The application of human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) from patients is expected in disease modeling and drug screening . Dilated cardiomyopathy (DCM) is an intractable disease characterized by the impairment of systolic function and leads to severe heart failure. A number of researchers have focused on disease modeling of DCM and reproduced its pathologic phenotypes in hiPSCMs, but a robust method to evaluate the contractile properties of cardiomyocytes has not been standardized. In addition, it is unknown whether the throughput of measurements and analyses could be increased sufficiently for compound screening. Here, we reviewed the articles in which the contractile abnormalities of DCM hiPSCMs were recapitulated and assessed the trends and problems in sample preparation and evaluation. We found that single-cell level analysis was ineffective in some cases, and a tissue engineering approach has become dominant recently because of its increased efficiency in reproducing impaired contractility. We also examined two commercially available automated measurement devices with moderate throughput for motion analysis using two-dimensional hiPSCM sheets composed of originally established DCM hiPSCMs. As a result, both of the tested devices, an impedance analyzer and a video image-based cell motion analyzer, were not effective in detecting the expected reduction of contractility in the DCM clone. These findings collectively suggest that a tissue engineering approach could expand the potential of disease modeling with hiPSCMs, and so far, appropriate methods for force measurement with sufficient throughput, but without sacrificing physiological fidelity, are awaited.
  
  Copyright © 2020 Ito, Nomura, Morita and Komuro.
  
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• Distinct Factors Secreted by Adipose Stromal Cells Protect the Endothelium From Barrier Dysfunction and Apoptosis.
  Front Cell Dev Biol

  2020 ;8():584653. doi: 10.3389/fcell.2020.584653.
  
  Lu Hongyan, Merfeld-Clauss Stephanie, Jawed Yameena, March Keith L, Coleman Michael E, Bogatcheva Natalia V,
  
  Abstract
  
  We have shown previously that adipose stromal cell (ASC)-derived conditioned media (CM) limited lung injury, endothelial barrier dysfunction, and apoptosis. Here, we used endothelial hyperpermeability and apoptosis assays to investigate how concentration processes affect endothelium-directed bioactivity of ASC-CM and to gain information on the nature of bioactive factors. Comparison of ASC-CM concentrated with differential molecular weight (MW) cutoff filters showed that endothelial barrier protection depended on the species-specific factors in ASC-CM fractionated with MW > 50 kDa. Known barrier regulators-keratin growth factor (KGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF)-were detected in ASC-CM fraction of > 100 kDa. Pretreatment of endothelial monolayers with concentrations of KGF, VEGF, and HGF detected in ASC-CM showed that only KGF and HGF protect the endothelium from barrier dysfunction. Depletion of KGF and HGF from ASC-CM attenuated ASC-CM's ability to protect the endothelial barrier. In contrast to barrier-protective factors, apoptosis-protective factors fractionated with MW < 3 kDa and were not species-specific. Application of donors of apoptosis-mitigating gases showed that the CO donor carbon monoxide-releasing molecule 2 (CORM2) protected the endothelium from apoptosis, while the HS donor NaSH did not. Knockdown of CO-generating heme oxygenase 1 in ASC attenuated ASC-CM's ability to protect the endothelium from apoptosis. We have shown that tumor necrosis factor alpha (TNF?)-induced apoptosis in endothelium is c-Jun N-terminal kinase (JNK)-dependent, and JNK activation is inhibited by ASC-CM pretreatment of endothelial cells. ASC-CM from heme oxygenase 1-depleted ASC displayed attenuated ability to suppress endothelial JNK activation, suggesting that CO-mediated protection of the endothelium from apoptosis is achieved by the downregulation of the JNK pathway. Altogether, our results demonstrate that the concentration of ASC-CM with low MW cutoff filters significantly reduces its anti-apoptotic activity while preserving its barrier-protective activity.
  
  Copyright © 2020 Lu, Merfeld-Clauss, Jawed, March, Coleman and Bogatcheva.
  
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• Plasmatic Membrane Expression of Adhesion Molecules in Human Cardiac Progenitor/Stem Cells Might Explain Their Superior Cell Engraftment after Cell Transplantation.
  Stem Cells Int

  2020 ;2020():8872009. doi: 10.1155/2020/8872009.
  
  Ontoria-Oviedo Imelda, Palacios Itziar, Panadero Joaquín, Sánchez Belén, García-García Francisco, López-Cerdán Adolfo, Dorronsoro Akaitz, Castellano Delia, Rodríguez-Borlado Luis, Bernad Antonio, Sepúlveda Pilar,
  
  Abstract
  
  Human bone marrow mesenchymal stem cells (BM-MSCs) and cardiac progenitor/stem cells (CPCs) have been extensively studied as a potential therapeutic treatment for myocardial infarction (MI). Previous reports suggest that lower doses of CPCs are needed to improve cardiac function relative to their bone marrow counterparts. Here, we confirmed this observations and investigated the surface protein expression profile that might explain this effect. Myocardial infarction was performed in nude rats by permanent ligation of the left coronary artery. Cardiac function and infarct size before and after cell transplantation were evaluated by echocardiography and morphometry, respectively. The CPC and BM-MSC receptome were analyzed by proteomic analysis of biotin-labeled surface proteins. Rats transplanted with CPCs showed a greater improvement in cardiac function after MI than those transplanted with BM-MSCs, and this was associated with a smaller infarct size. Analysis of the receptome of CPCs and BM-MSCs showed that gene ontology biological processes and KEGG pathways associated with adhesion mechanisms were upregulated in CPCs compared with BM-MSCs. Moreover, the membrane protein interactome in CPCs showed a strong relationship with biological processes related to cell adhesion whereas the BM-MSCs interactome was more related to immune regulation processes. We conclude that the stronger capacity of CPCs over BM-MSCs to engraft in the infarcted area is likely linked to a more pronounced cell adhesion expression program.
  
  Copyright © 2020 Imelda Ontoria-Oviedo et al.
  
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• miR-137 boosts the neuroprotective effect of endothelial progenitor cell-derived exosomes in oxyhemoglobin-treated SH-SY5Y cells partially via COX2/PGE2 pathway.
  Stem Cell Res Ther

  2020 Oct;11(1):330. doi: 10.1186/s13287-020-01836-y.
  
  Li Yuchen, Wang Jinju, Chen Shuzhen, Wu Pei, Xu Shancai, Wang Chunlei, Shi Huaizhang, Bihl Ji,
  
  Abstract
  
  BACKGROUND:
  We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured SH-SY5Y cells.
  
  METHODS:
  The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs, and neurons. The uptake mechanisms of EPC-EXs in SH-SY5Y cells were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002, and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression.
  
  RESULTS:
  The present work showed (1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; (2) miR-137 was decreased in neurons after oxyHb treatment, and EXs could restore the miR-137 levels; (3) EXs worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; (4) EXs are more effective in improving the cellular MMP, ROS, and ATP level; (5) EXs, but not EXs, protected oxyHb-treated SH-SY5Y cells against lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4; and (6) EXs suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXs.
  
  CONCLUSION:
  miR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated SH-SY5Y cells. Furthermore, EXs rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.
  
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• Reaching out to stakeholders: The use of knowledge terminology on the websites of Australian public hospitals.
  BMC Health Serv Res

  2020 Oct;20(1):974. doi: 10.1186/s12913-020-05798-y.
  
  Miklosik Andrej, Evans Nina,
  
  Abstract
  
  BACKGROUND:
  The objective of the study described in this article was to examine whether, and to what extent, Australian public hospitals use knowledge terminology, i.e. a body of knowledge-related terms, on their websites. The paper also discusses the difference in the level of such communication between large and small hospitals, the factors affecting the use of the knowledge-related terms in the communication and the similarities/differences between the use of knowledge terms in Australian public hospitals and large/small companies in Australia.
  
  METHODS:
  151 Australian public hospitals were included in the research sample: 51 large and 100 small hospitals. Using the method of content analysis, websites mentioning knowledge creation, knowledge sharing, knowledge implementation, and knowledge retention were identified, along with the number of these mentions. Descriptive statistics and chi square test of independence were used to provide answers to four research questions.
  
  RESULTS:
  Of the 151 hospitals included in the sample, 30 had no website and 62 (50 small and 12 large) had a single page website. The study found that there are differences between Australian public hospitals regarding the level of their knowledge communication on their websites, both between small and large hospitals and between the individual hospitals within the large and small hospital groups.
  
  CONCLUSIONS:
  A well-known saying goes "For the mouth speaks what the heart is full of". Effective communication of knowledge-related terminologies to both internal and external stakeholders, i.e. the parties who access the websites, is therefore an indication of a knowledge focus in the public hospitals. Large hospitals are generally more active in communicating knowledge terms, although there are some exceptions. Some of the small hospitals can lead by example, but most of them do not include knowledge terminology in their communication on websites.
  
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• Solid Organ Transplantation.
  Hematol Oncol Clin North Am

  2020 Dec;34(6):1161-1175. doi: S0889-8588(20)30101-5.
  
  Bal Susan, Landau Heather J,
  
  Abstract
  
  Please add expansion for AL. Hematologic disease control combined with solid organ transplantation can result in long-term survival in selected patients with light chain (AL) amyloidosis and limited other organ involvement. Restoration of critical cardiac function with organ transplantation can render patients eligible for effective disease-directed therapies, including high-dose therapy and autologous stem cell transplantation. Access to directed-donor organs, exchange programs for renal transplantation, and extended-donor organs for cardiac transplantation improves the availability of organs for patients with AL amyloidosis. Disease recurrence in the graft and progression in other organs remain concerns but often can be managed with a variety of effective plasma cell-directed therapies.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Options for Chemotherapy and Scoring Response and Relapse.
  Hematol Oncol Clin North Am

  2020 Dec;34(6):1115-1131. doi: S0889-8588(20)30082-4.
  
  Varga Cindy, Chaulagain Chakra,
  
  Abstract
  
  Chemotherapy for amyloid light chain (AL) amyloidosis has evolved over the years. Although high-dose melphalan and stem cell transplantation remain the standard of care for eligible patients, a vast majority of the patients at the time of presentation are not eligible for this approach and require low-intensity but highly effective induction therapy, usually based on bortezomib. Immunomodulatory agents are not well tolerated, particularly by patients with AL amyloidosis cardiomyopathy, and are reserved for second-line or later therapy. Because there currently is no Food Drug and Administration-approved therapy, participation in well-designed clinical trials of high scientific merit should be considered.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Autologous stem cell transplantation following simultaneous liver and kidney transplantation in severe amyloid light chain amyloidosis associated with multiple myeloma: a case report.
  J Med Case Rep

  2020 Oct;14(1):201. doi: 10.1186/s13256-020-02511-9.
  
  Al-Zoairy R, Viveiros A, Zoller H, Schneeberger S, Oberhuber G, Gunsilius E, Tilg H, Wolf D, Rudzki J D,
  
  Abstract
  
  INTRODUCTION:
  The involvement of vital organs in multiple myeloma (MM) with systemic amyloid light-chain (AL) amyloidosis can lead to acute organ failure. In this case, the fear of recurrence or progression of multiple myeloma often excludes those patients from undergoing organ transplantation. Nevertheless, clinically fit patients might benefit from a different therapeutic approach. This case presentation might highlight this particular unmet need and strengthen a different treatment approach.
  
  CASE PRESENTATION:
  To our knowledge, we present the first case of successful simultaneous liver and kidney transplantation, followed by autologous stem cell transplantation in a 60-year-old Caucasian male patient suffering from MM (Durie-Salmon stage IIB; ISS-stage: III, RISS stage: III) with primary AL amyloidosis. Chemotherapy treatment led to end-stage kidney disease requiring dialysis. Liver failure also occurred after at least three cycles of CyBorD (bortezomib, cyclophosphamide, and dexamethasone) of induction therapy with a good hematologic response. Over three years after the initial diagnosis, the patient is reportedly showing an excellent quality of life and a complete remission.
  
  DISCUSSION AND CONCLUSION:
  We conclude that kidney and liver transplantation followed by autologous stem cell transplantation can be a treatment option for a selected group of patients with MM if AL amyloidosis is leading. In the end, the remission assessment by IMWG response criteria displayed a complete remission of MM together with complete reconstitution of organ functions (liver & renal function) as long as upfront clinical evaluation excludes significant cardiac involvement and other severe co-morbidities.
  
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• Generation of iPSC lines from peripheral blood mononuclear cells of identical twins both suffering from type 2 diabetes mellitus and one of them additionally diagnosed with atherosclerosis.
  Stem Cell Res

  2020 Oct;49():102051. doi: S1873-5061(20)30352-4.
  
  Szabó Eszter, Reé Dóra, Jezsó Bálint, Vincze Katalin, Földes Gábor, Molnár Andrea Á, Réthelyi János M, Apáti Ágota,
  
  Abstract
  
  Here we describe the generation of induced pluripotent stem cell (iPSC) lines from peripheral blood samples of identical twin sisters with type 2 diabetes mellitus (DM2). Two clonal lines from each patient (HU-DM2-A-1, HU-DM2-A-2 and HU-DM2-B-1, HU-DM2-B-2) were established via Sendai viral reprograming of peripheral blood mononuclear cells, and characterized to confirm pluripotency and genetic integrity. The established iPSC lines can help to investigate DM2 related cellular phenotypes and provide a model system for drug testing.
  
  Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
  
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• Brachyury engineers cardiac repair competent stem cells.
  Stem Cells Transl Med

  2020 Oct;():. doi: 10.1002/sctm.20-0193.
  
  Li Mark, Yamada Satsuki, Shi Ao, Singh Raman Deep, Rolland Tyler J, Jeon Ryounghoon, Lopez Natalia, Shelerud Lukas, Terzic Andre, Behfar Atta,
  
  Abstract
  
  To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In?vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In?vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600?000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.
  
  © 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.
  
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• Novel mutations of TCTN3/LTBP2 with cellular function changes in congenital heart disease associated with polydactyly.
  J Cell Mol Med

  2020 Oct;():. doi: 10.1111/jcmm.15950.
  
  Chen Huan-Xin, Yang Zi-Yue, Hou Hai-Tao, Wang Jun, Wang Xiu-Li, Yang Qin, Liu Lin, He Guo-Wei,
  
  Abstract
  
  Congenital heart disease (CHD) associated with polydactyly involves various genes. We aimed to identify variations from genes related to complex CHD with polydactyly and to investigate the cellular functions related to the mutations. Blood was collected from a complex CHD case with polydactyly, and whole exome sequencing (WES) was performed. The CRISPR/Cas9 system was used to generate human pluripotent stem cell with mutations (hPSCs-Mut) that were differentiated into cardiomyocytes (hPSC-CMs-Mut) and analysed by transcriptomics on day 0, 9 and 13. Two heterozygous mutations, LTBP2 (c.2206G>A, p.Asp736Asn, RefSeq NM_000428.2) and TCTN3 (c.1268G>A, p.Gly423Glu, RefSeq NM_015631.5), were identified via WES but no TBX5 mutations were found. The stable cell lines of hPSCs-LTBP2 /TCTN3 were constructed and differentiated into hPSC-CMs-LTBP2 /TCTN3 . Compared to the wild type, LTBP2 mutation delayed the development of CMs. The TCTN3 mutation consistently presented lower rate and weaker force of the contraction of CMs. For gene expression pattern of persistent up-regulation, pathways in cardiac development and congenital heart disease were enriched in hPSCs-CM-LTBP2 , compared with hPSCs-CM-WT. Thus, the heterozygous mutations in TCTN3 and LTBP2 affect contractility (rate and force) of cardiac myocytes and may affect the development of the heart. These findings provide new insights into the pathogenesis of complex CHD with polydactyly.
  
  © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
  
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• A Concise Review on Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Personalized Regenerative Medicine.
  Stem Cell Rev Rep

  2020 Oct;():. doi: 10.1007/s12015-020-10061-2.
  
  Pushp Pallavi, Nogueira Diogo E S, Rodrigues Carlos A V, Ferreira Frederico C, Cabral Joaquim M S, Gupta Mukesh Kumar,
  
  Abstract
  
  The induced pluripotent stem cells (iPSCs) are derived from somatic cells by using reprogramming factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM) or Oct4, Sox2, Nanog and Lin28 (OSNL). They resemble embryonic stem cells (ESCs) and have the ability to differentiate into cell lineage of all three germ-layer, including cardiomyocytes (CMs). The CMs can be generated from iPSCs by inducing embryoid bodies (EBs) formation and treatment with activin A, bone morphogenic protein 4 (BMP4), and inhibitors of Wnt signaling. However, these iPSC-derived CMs are a heterogeneous population of cells and require purification and maturation to mimic the in vivo CMs. The matured CMs can be used for various therapeutic purposes in regenerative medicine by cardiomyoplasty or through the development of tissue-engineered cardiac patches. In recent years, significant advancements have been made in the isolation of iPSC and their differentiation, purification, and maturation into clinically usable CMs. Newer small molecules have also been identified to substitute the reprogramming factors for iPSC generation as well as for direct differentiation of somatic cells into CMs without an intermediary pluripotent state. This review provides a concise update on the generation of iPSC-derived CMs and their application in personalized cardiac regenerative medicine. It also discusses the current limitations and challenges in the application of iPSC-derived CMs. Graphical abstract.
  
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