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Pubblicazioni recenti - cardiac stem
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Suppression of inflammation and fibrosis using soluble epoxide hydrolase inhibitors enhances cardiac stem cell-based therapy.
Stem Cells Transl Med2020 Aug;():. doi: 10.1002/sctm.20-0143.
Sirish Padmini, Thai Phung N, Lee Jeong Han, Yang Jun, Zhang Xiao-Dong, Ren Lu, Li Ning, Timofeyev Valeriy, Lee Kin Sing Stephen, Nader Carol E, Rowland Douglas J, Yechikov Sergey, Ganaga Svetlana, Young Nilas, Lieu Deborah K, Yamoah Ebenezer N, Hammock Bruce D, Chiamvimonvat Nipavan,
Abstract
Stem cell replacement offers a great potential for cardiac regenerative therapy. However, one of the critical barriers to stem cell therapy is a significant loss of transplanted stem cells from ischemia and inflammation in the host environment. Here, we tested the hypothesis that inhibition of the soluble epoxide hydrolase (sEH) enzyme using sEH inhibitors (sEHIs) to decrease inflammation and fibrosis in the host myocardium may increase the survival of the transplanted human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in a murine postmyocardial infarction model. A specific sEHI (1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea [TPPU]) and CRISPR/Cas9 gene editing were used to test the hypothesis. TPPU results in a significant increase in the retention of transplanted cells compared with cell treatment alone. The increase in the retention of hiPSC-CMs translates into an improvement in the fractional shortening and a decrease in adverse remodeling. Mechanistically, we demonstrate a significant decrease in oxidative stress and apoptosis not only in transplanted hiPSC-CMs but also in the host environment. CRISPR/Cas9-mediated gene silencing of the sEH enzyme reduces cleaved caspase-3 in hiPSC-CMs challenged with angiotensin II, suggesting that knockdown of the sEH enzyme protects the hiPSC-CMs from undergoing apoptosis. Our findings demonstrate that suppression of inflammation and fibrosis using an sEHI represents a promising adjuvant to cardiac stem cell-based therapy. Very little is known regarding the role of this class of compounds in stem cell-based therapy. There is consequently an enormous opportunity to uncover a potentially powerful class of compounds, which may be used effectively in the clinical setting.
© 2020 The Authors. STEM CELLS Translational Medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press.
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Phenyl saligenin phosphate disrupts cell morphology and the actin cytoskeleton in differentiating H9c2 cardiomyoblasts and human induced pluripotent stem cell derived cardiomyocyte progenitor cells.
Chem Res Toxicol2020 Aug;():. doi: 10.1021/acs.chemrestox.0c00100.
Felemban Shatha G, Vyas Falguni S, Durose Lyndsey J, Hargreaves Alan Jeffrey, Dickenson John Michael,
Abstract
We have previously shown that phenyl saligenin phosphate (PSP), an organophosphorus compound which is classed as a weak inhibitor of acetylcholinesterase, triggered cytotoxicity in mitotic and differentiated H9c2 cardiomyoblasts. The aim of this study was to assess whether sub-lethal concentrations of PSP could disrupt the morphology of differentiating rat H9c2 cardiomyoblasts and human induced pluripotent stem cell-derived cardiomyocyte progenitor cells (hiPSC-CMs), and to assess the underlying cytoskeletal changes. PSP-induced changes in protein expression were monitored via Western blotting, immunocytochemistry, and proteomic analysis. PSP mediated cytotoxicity was determined by measuring MTT reduction, LDH release and caspase-3 activity. Sub-lethal exposure to PSP (3 µM) induced morphological changes in differentiating H9c2 cells (7, 9 and 13 days), reflected by reduced numbers of spindle-shaped cells. Moreover, this treatment (7 days) attenuated the expression of the cytoskeletal proteins cardiac troponin I, tropomyosin-1 and ?-actin. Further proteomic analysis identified nine proteins (e.g. heat shock protein 90-? and calumenin) which were down-regulated by PSP exposure in H9c2 cells. To assess the cytotoxic effects of organophosphorus compounds in a human cell model, we determined their effects on human induced pluripotent stem cell-derived cardiomyocyte progenitor cells. Chlorpyrifos and diazinon-induced cytotoxicity (48 h) was evident only at concentrations >100 µM. By contrast, PSP exhibited cytotoxicity in hiPSC-CMs at a concentration of 25 µM following 48 h exposure. Finally, sub-lethal exposure to PSP (3 µM; 7 days) induced morphological changes and decreased the expression of cardiac troponin I, tropomyosin-1 and ?-actin in hiPSC-CMs. In summary, our data suggest cardiomyocyte morphology is disrupted in both cell models by sub-lethal concentrations of PSP via modulation of cytoskeletal protein expression.
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Correction to: Sca-1-Positive Cardiac Stem Cell Migration in a Cardiac Infarction Model.
Inflammation2020 Aug;():. doi: 10.1007/s10753-020-01315-9.
Liu Jingjin, Wang Yongshun, Du Wenjuan, Yu Bo,
Abstract
After publication of our article [1], we became aware that there were errors in Fig. 1, namely that the Echocardiographic assessment of 1w, 2w, and 4w groups was incorrectly presented.
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From Human Pluripotent Stem Cells to 3D Cardiac Microtissues: Progress, Applications and Challenges.
Bioengineering (Basel)2020 Aug;7(3):. doi: E92.
Branco Mariana A, Cabral Joaquim M S, Diogo Maria Margarida,
Abstract
The knowledge acquired throughout the years concerning the in vivo regulation of cardiac development has promoted the establishment of directed differentiation protocols to obtain cardiomyocytes (CMs) and other cardiac cells from human pluripotent stem cells (hPSCs), which play a crucial role in the function and homeostasis of the heart. Among other developments in the field, the transition from homogeneous cultures of CMs to more complex multicellular cardiac microtissues (MTs) has increased the potential of these models for studying cardiac disorders in vitro and for clinically relevant applications such as drug screening and cardiotoxicity tests. This review addresses the state of the art of the generation of different cardiac cells from hPSCs and the impact of transitioning CM differentiation from 2D culture to a 3D environment. Additionally, current methods that may be employed to generate 3D cardiac MTs are reviewed and, finally, the adoption of these models for in vitro applications and their adaptation to medium- to high-throughput screening settings are also highlighted.
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Transfection of hPSC-Cardiomyocytes Using Viafect? Transfection Reagent.
Methods Protoc2020 Aug;3(3):. doi: E57.
Bodbin Sara E, Denning Chris, Mosqueira Diogo,
Abstract
Twenty years since their first derivation, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have shown promise in disease modelling research, while their potential for cardiac repair is being investigated. However, low transfection efficiency is a barrier to wider realisation of the potential this model system has to offer. We endeavoured to produce a protocol for improved transfection of hPSC-CMs using the Viafect reagent by Promega. Through optimisation of four essential parameters: (i) serum supplementation, (ii) time between replating and transfection, (iii) reagent to DNA ratio and (iv) cell density, we were able to successfully transfect hPSC-CMs to ~95% efficiencies. Transfected hPSC-CMs retained high purity and structural integrity despite a mild reduction in viability, and preserved compatibility with phenotyping assays of hypertrophy. This protocol greatly adds value to the field by overcoming limited transfection efficiencies of hPSC-CMs in a simple and quick approach that ensures sustained expression of transfected genes for at least 14 days, opening new opportunities in mechanistic discovery for cardiac-related diseases.
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A review on qualifications and cost effectiveness of induced pluripotent stem cells (IPSCs)-induced cardiomyocytes in drug screening tests.
Arch Physiol Biochem2020 Aug;():1-12. doi: 10.1080/13813455.2020.1802600.
Malihi Golrokh, Nikoui Vahid, Elson Elliot L,
Abstract
Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in disease modelling, preclinical evaluation of drug therapy and pharmaco-toxicological testing. Since the discovery of iPSCs in 2006, many advanced techniques have been introduced to differentiate iPSCs to cardiomyocytes, which have been progressively improved. The disease models from iPSC-induced cardiomyocytes (iPSC-CM) have been successfully helping to study a variety of cardiac diseases such as long QT syndrome, drug-induced long QT, different cardiomyopathies related to mutations in mitochondria or desmosomal proteins and other rare genetic diseases. IPSC-CMs have also been used to screen the role of chemicals in cardiovascular drug discovery and individualisation of drug dosages. In this review, the quality of current procedures for characterisation and maturation of iPSC-CM lines will be discussed. Also, we will focus on time efficiency and cost of standard differentiation methods after reprogramming.
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Stem Cells and Lung Regeneration.
Am J Physiol Cell Physiol2020 Aug;():. doi: 10.1152/ajpcell.00036.2020.
Parekh Kalpaj R, Nawroth Janna, Pai Albert, Busch Shana M, Senger Christiana N, Ryan Amy L,
Abstract
Summary/Abstract The ability to replace defective cells in an airway with cells that can engraft, integrate and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives, is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.
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A hypertension patient derived induced pluripotent stem cell model demonstrates a role for GPER in hypertension risk and development.
Am J Physiol Cell Physiol2020 Aug;():. doi: 10.1152/ajpcell.00350.2019.
Fredette Natalie C, Malik Eliyah, Mukhtar Marah L, Prossnitz Eric R, Terada Naohiro,
Abstract
Hypertension (HTN) is a polyfactorial disease that can manifest severe cardiovascular pathologies such as heart failure or stroke. Genome Wide Association Studies (GWAS) of HTN indicate that single nucleotide polymorphisms (SNPs) contribute to increased risk for HTN and resistance to some HTN drug regimens (19, 26, 35, 52). However, cellular mechanistic insights of such SNPs remain largely unknown. Using a HTN patient-derived induced pluripotent stem cell (iPSC) bank and CRISPR/Cas9-mediated gene editing approach, we investigated the effects of a female HTN risk-associated SNP (rs1154431) of the G protein-coupled estrogen receptor (GPER) (5) in vascular endothelial cells. Although GPER deletion reduced eNOS activation in iPSC-derived endothelial cells (iEC), the polymorphism itself did not significantly affect eNOS and NO production in a comparison of isogenic hemizygous iECs expressing either normal (P16) or HTN-associated (L16) GPER. Interestingly, we demonstrate for the first time that GPER plays a role in regulation of adhesion molecule expression and monocyte adhesion to iECs. Moreover, the L16 iECs had higher expression of inflammation genes over P16 iECs, implying that the risk variant may affect carrier individuals through increased inflammatory activity. This study further indicates that iPSC are a useful platform for exploring mechanistic insights underlying hypertension GWAS endeavors.
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Laminin-221 Enhances Therapeutic Effects of Human-Induced Pluripotent Stem Cell-Derived 3-Dimensional Engineered Cardiac Tissue Transplantation in a Rat Ischemic Cardiomyopathy Model.
J Am Heart Assoc2020 Aug;():e015841. doi: 10.1161/JAHA.119.015841.
Samura Takaaki, Miyagawa Shigeru, Kawamura Takuji, Fukushima Satsuki, Yokoyama Jun-Ya, Takeda Maki, Harada Akima, Ohashi Fumiya, Sato-Nishiuchi Ryoko, Toyofuku Toshihiko, Toda Koichi, Sekiguchi Kiyotoshi, Sawa Yoshiki,
Abstract
Background Extracellular matrix, especially laminin-221, may play crucial roles in viability and survival of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) after in vivo transplant. Then, we hypothesized laminin-221 may have an adjuvant effect on therapeutic efficacy by enhancing cell viability and survival after transplantation of 3-dimensional engineered cardiac tissue (ECT) to a rat model of myocardial infarction. Methods and Results In vitro study indicates the impacts of laminin-221 on hiPS-CMs were analyzed on the basis of mechanical function, mitochondrial function, and tolerance to hypoxia. We constructed 3-dimensional ECT containing hiPS-CMs and fibrin gel conjugated with laminin-221. Heart function and in vivo behavior were assessed after engraftment of 3-dimensional ECT (laminin-conjugated ECT, n=10; ECT, n=10; control, n=10) in a rat model of myocardial infarction. In vitro assessment indicated that laminin-221 improves systolic velocity, diastolic velocity, and maximum capacity of oxidative metabolism of hiPS-CMs. Cell viability and lactate dehydrogenase production revealed that laminin-221 improved tolerance to hypoxia. Furthermore, analysis of mRNA expression revealed that antiapoptotic genes were upregulated in the laminin group under hypoxic conditions. Left ventricular ejection fraction of the laminin-conjugated ECT group was significantly better than that of other groups 4 weeks after transplantation. Laminin-conjugated ECT transplantation was associated with significant improvements in expression levels of rat vascular endothelial growth factor. In early assessments, cell survival was also improved in laminin-conjugated ECTs compared with ECT transplantation without laminin-221. Conclusions In vitro laminin-221 enhanced mechanical and metabolic function of hiPS-CMs and improved the therapeutic impact of 3-dimensional ECT in a rat ischemic cardiomyopathy model. These findings suggest that adjuvant laminin-221 may provide a clinical benefit to hiPS-CM constructs.
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Intron with transgenic marker (InTraM) facilitates high-throughput screening of endogenous gene reporter lines.
Genesis2020 Aug;():e23391. doi: 10.1002/dvg.23391.
Collins Russell T, Coxam Baptiste, Fechner Ines, Unterweger Iris, Szymborska Anna, Meier Katja, Gerhardt Holger,
Abstract
The generation and maintenance of genome edited zebrafish lines is typically labor intensive due to the lack of an easy visual read-out for the modification. To facilitate this process, we have developed a novel method that relies on the inclusion of an artificial intron with a transgenic marker (InTraM) within the knock-in sequence of interest, which upon splicing produces a transcript with a precise and seamless modification. We have demonstrated this technology by replacing the stop codon of the zebrafish fli1a gene with a transcriptional activator KALTA4, using an InTraM that enables red fluorescent protein expression in the heart.
© 2020 The Authors. genesis published by Wiley Periodicals LLC????.
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Stem Cell Therapy for Chronic and Advanced Heart Failure.
Curr Heart Fail Rep2020 Aug;():. doi: 10.1007/s11897-020-00477-9.
Poglajen Gregor, Frljak Sabina, Zemlji? Gregor, Cerar Andra?, Okraj?ek Renata, ?ebe?tjen Miran, Vrtovec Bojan,
Abstract
PURPOSE OF REVIEW:
The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD).
RECENT FINDINGS:
In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.
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Aligned nanofiber scaffolds improve functionality of cardiomyocytes differentiated from human induced pluripotent stem cell-derived cardiac progenitor cells.
Sci Rep2020 Aug;10(1):13575. doi: 10.1038/s41598-020-70547-4.
Ding Mei, Andersson Henrik, Martinsson Sofia, Sabirsh Alan, Jonebring Anna, Wang Qing-Dong, Plowright Alleyn T, Drowley Lauren,
Abstract
Cardiac progenitor cells (CPCs), capable of differentiating into multiple cardiac cell types including cardiomyocytes (CMs), endothelial cells, and smooth muscle cells, are promising candidates for cardiac repair/regeneration. In vitro model systems where cells are grown in a more in vivo-like environment, such as 3D cultures, have been shown to be more predictive than 2D culture for studying cell biology and disease pathophysiology. In this report, we focused on using Wnt inhibitors to study the differentiation of human iPSC-CPCs under 2D or 3D culture conditions by measuring marker protein and gene expression as well as intracellular Ca oscillation. Our results show that the 3D culture with aligned nanofiber scaffolds, mimicing the architecture of the extracellular matrix of the heart, improve the differentiation of iPSC-CPCs to functional cardiomyocytes induced by Wnt inhibition, as shown with increased number of cardiac Troponin T (cTnT)-positive cells and synchronized intracellular Ca oscillation. In addition, we studied if 3D nanofiber culture can be used as an in vitro model for compound screening by testing a number of other differentiation factors including a ALK5 inhibitor and inhibitors of BMP signaling. This work highlights the importance of using a more relevant in vitro model and measuring not only the expression of marker proteins but also the functional readout in a screen in order to identify the best compounds and to investigate the resulting biology.
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Integrative Genomic Analysis Reveals Four Protein Biomarkers for Platelet Traits.
Circ Res2020 Aug;():. doi: 10.1161/CIRCRESAHA.119.316447.
Lee Dong Heon, Yao Chen, Bhan Arunoday, Schlaeger Thorsten M, Keefe Joshua, Rodriguez Benjamin At, Hwang Shih-Jen, Chen Ming-Huei, Levy Daniel, Johnson Andrew D,
Abstract
Mean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms. We aimed to identify causal protein biomarkers for MPV and PLT among 71 CVD-related plasma proteins measured in Framingham Heart Study (FHS) participants. We conducted integrative analyses of genetic variants associated with PLT/MPV with protein quantitative trait locus variants associated with plasma proteins followed by Mendelian randomization to infer causal relations of proteins for PLT/MPV. We also tested protein-PLT/MPV association in FHS participants. Utilizing induced pluripotent stem cell-derived megakaryocyte (MK) clones that produce functional platelets, we conducted RNA-sequencing and analyzed expression differences between low- and high-platelet producing clones. We then performed small interfering RNA gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in MK clones to examine effects on platelet production. In protein-trait association analyses, ten proteins were associated with MPV and 31 with PLT. MR identified four putatively causal proteins for MPV and four for PLT. Glycoprotein V (GP5), granulin (GRN), and melanoma cell adhesion molecule (MCAM) were associated with PLT, while myeloperoxidase (MPO) showed significant association with MPV in both analyses. RNA-sequencing analysis results were directionally concordant with observed and MR-inferred associations for GP5, GRN, and MCAM. In siRNA gene knockdown experiments, silencing GP5, GRN, and MPO decreased platelet counts. Genome-wide association study results suggest several of these may be linked to CVD risk. We identified four proteins that are causally linked to platelet counts. These proteins may also have roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.
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An inhibitor role of Nrf2 in the regulation of myocardial senescence and dysfunction after myocardial infarction.
Life Sci2020 Aug;():118199. doi: S0024-3205(20)30951-6.
Luo Xinxia, Zhou Junyang, Wang Zhixiao, He Yun, Yu Li, Ma Shinan, Wang Shan, Wang Xiaoli, Yuan Yahong, Li Dongsheng, Cui Taixing, Ding Yan,
Abstract
Cellular senescence, a process whereby cells enter a state of permanent growth arrest, appears to regulate cardiac pathological remodeling and dysfunction in response to various stresses including myocardial infarction (MI). However, the precise role as well as the underlying regulatory mechanism of cardiac cellular senescence in the ischemic heart disease remain to be further determined. Herein we report an inhibitory role of Nrf2, a key transcription factor of cellular defense, in regulating cardiac senescence in infarcted hearts as well as a therapeutic potential of targeting Nrf2-mediated suppression of cardiac senescence in the treatment of MI-induced cardiac dysfunction. MI was induced by left coronary artery ligation for 28?days in mice. Heart tissues from the infarct border zone were used for the analyses. The MI-induced cardiac dysfunction was associated with increased myocardial cell senescence, oxidative stress and apoptosis in adult wild type (WT) mice. In addition, a downregulated Nrf2 activity was associated with upregulated Keap1 levels and increased phosphorylation of JAK and FYN in the infarcted border zone heart tissues. Nrf2 Knockout (Nrf2) enhanced the MI-induced myocardial, cardiac dysfunction and senescence. Qiliqiangxin (QLQX), a herbal medicine which could reverse the MI-induced suppression of Nrf2 activity, significantly inhibited the MI-induced cardiac senescence, apoptosis, and cardiac dysfunction in WT mice but not in Nrf2 mice. These results indicate that MI downregulates Nrf2 activity thus promoting oxidative stress to accelerate cellular senescence in the infarcted heart towards cardiac dysfunction and Nrf2 may be a drug target for suppressing the cellular senescence-associated pathologies in infarcted hearts.
Copyright © 2020. Published by Elsevier Inc.
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Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.
Brain2020 Aug;():. doi: awaa206.
Hedberg-Oldfors Carola, Meyer Robert, Nolte Kay, Abdul Rahim Yassir, Lindberg Christopher, Karason Kristjan, Thuestad Inger Johanne, Visuttijai Kittichate, Geijer Mats, Begemann Matthias, Kraft Florian, Lausberg Eva, Hitpass Lea, Götzl Rebekka, Luna Elizabeth J, Lochmüller Hanns, Koschmieder Steffen, Gramlich Michael, Gess Burkhard, Elbracht Miriam, Weis Joachim, Kurth Ingo, Oldfors Anders, Knopp Cordula,
Abstract
The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
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Significant role of magnetic resonance imaging for the diagnosis and evaluation of cardiac amyloidosis in primary light chain amyloidosis.
J Clin Exp Hematop2020 Aug;():. doi: 10.3960/jslrt.19040.
Sekiguchi Yasunobu, Wakabayashi Mutsumi, Iizuka Hiroko, Takizawa Haruko, Sugimoto Keiji, Sakajiri Sakura, Inano Tadaaki, Fukuda Yasutaka, Hamano Yasuharu, Tomita Shigeki, Izumi Hiroshi, Isogai Hiroyuki, Okubo Mitsuo, Nakamura Noriko, Sawada Tomohiro, Matsumoto Kimihiro, Noguchi Masaaki,
Abstract
A 47-year-old male with macroglossia presented with dyspnea on effort and chest pain at rest. Cardiac MRI revealed diffuse global subendocardial late gadolinium enhancement below the left ventricular endocardium and a dark blood pool of intracardiac contrast medium. Tongue biopsy revealed amyloid deposition, which was limited in the myocardium. He was diagnosed with primary light chain amyloidosis. His condition was stage I according to the Mayo Clinic staging system. He underwent autologous peripheral blood stem cell transplantation. On Day 10, he developed chest pain and died suddenly on Day 11. Postmortem examination revealed amyloid deposition throughout the heart.
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The effects of ? and ? adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise.
Cell Stress Chaperones2020 Aug;():. doi: 10.1007/s12192-020-01136-7.
Kunz Hawley E, Agha Nadia H, Hussain Maryam, LaVoy Emily C, Smith Kyle A, Mylabathula Preteesh, Diak Douglass, Baker Forrest L, O'Connor Daniel P, Bond Richard A, Katsanis Emmanuel, Bollard Catherine M, Simpson Richard J,
Abstract
The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if ? adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n?=?12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a ? AR antagonist (nadolol) or a ? AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (? VSTs/100,000 CD3 T cells?=?93?±?104 vs. 22?±?91 for placebo and nadolol, respectively; p?=?0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially ? AR mediated, thus highlighting a role for the ? AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent ? AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.
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Cardiac Regeneration After Myocardial Infarction: an Approachable Goal.
Curr Cardiol Rep2020 Aug;22(10):122. doi: 10.1007/s11886-020-01361-7.
Giacca Mauro,
Abstract
PURPOSE OF REVIEW:
Until recently, cardiac regeneration after myocardial infarction has remained a holy grail in cardiology. Failure of clinical trials using adult stem cells and scepticism about the actual existence of such cells has reinforced the notion that the heart is an irreversibly post-mitotic organ. Recent evidence has drastically challenged this conclusion.
RECENT FINDINGS:
Cardiac regeneration can successfully be obtained by at least two strategies. First, new cardiomyocytes can be generated from embryonic stem cells or induced pluripotent stem cells and administered to the heart either as cell suspensions or upon ex vivo generation of contractile myocardial tissue. Alternatively, the endogenous capacity of cardiomyocytes to proliferate can be stimulated by the delivery of individual genes or, more successfully, of selected microRNAs. Recent experimental success in large animals by both strategies now fuels the notion that cardiac regeneration is indeed possible. Several technical hurdles, however, still need to be addressed and solved before broad and successful clinical application is achieved.
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A field-based quantitative analysis of sublethal effects of air pollution on pollinators.
Proc Natl Acad Sci U S A2020 Aug;():. doi: 202009074.
Thimmegowda Geetha G, Mullen Susan, Sottilare Katie, Sharma Ankit, Mohanta Saptashi Soham, Brockmann Axel, Dhandapany Perundurai S, Olsson Shannon B,
Abstract
While the impact of air pollution on human health is well studied, mechanistic impacts of air pollution on wild systems, including those providing essential ecosystem services, are largely unknown, but directly impact our health and well-being. India is the world's largest fruit producer, second most populous country, and contains 9 of the world's 10 most polluted cities. Here, we sampled Giant Asian honey bees, , at locations with varying air pollution levels in Bangalore, India. We observed significant correlations between increased respirable suspended particulate matter (RSPM) deposition and changes in bee survival, flower visitation, heart rate, hemocyte levels, and expression of genes related to lipid metabolism, stress, and immunity. Lab-reared exposed to these same sites also exhibited similar molecular and physiological differences. Our study offers a quantitative analysis on the current impacts of air pollution on insects, and indicates the urgency for more nonhuman studies to accurately assess the effects of pollution on our natural world.
Copyright © 2020 the Author(s). Published by PNAS.
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Umbilical cord mesenchymal stromal cells engraft and transdifferentiate into cardiomyocyte-like cells following acute myocardial ischemia?.
Acta Histochem2020 Sep;122(6):151578. doi: S0065-1281(20)30077-5.
Yigman Zeynep, Ozdemir Elif Derya, Turan Nilufer N, Ulus A Tulga, Can Alp,
Abstract
OBJECTIVE:
Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) gained importance in acute/chronic ischemic cardiomyopathy because of their outstanding regenerative potential in various pathologic conditions. The present study was designed to determine to what extent hUC-MSCs contribute to myocardial regeneration in acute experimental myocardial infarction (MI) in rats.
METHODS:
Animals were assigned into two groups; the control group received intramyocardial PBS injections, while the hUC-MSC group received calcein-AM-labeled 8.8 × 10/kg hUC-MSCs. Three weeks following the acute MI induction, rats were sacrificed after assessing the left ventricular (LV) function using echocardiography. For the assessment of infarct size, the triphenyl tetrazolium chloride (TTC) test was used in isolated hearts. Collagen-rich scar tissue was demonstrated using Masson's trichrome staining, followed by the detection of cardiac troponin I (cTnI), ?-sarcomeric actin (?-SA), von Willebrand factor (vWF), CD68 and CD206 expressions in control and cell-injected sections.
RESULTS:
Echocardiography revealed a significant difference (P = 0.037) in the LV ejection fraction between groups. TTC assays demonstrated a significant difference (P = 0.006) between the groups regarding the ratio of the infarcted LV area. Calcein-AM-loaded cells were identified mostly in ischemic myocardium. Transplanted cells also expressed human-specific cTnI, providing concrete proof of transdifferentiation into cardiomyocytes, and ?-SA. vWF cells verified the neovascularization in the ischemic myocardium. Finally, a slight shift from pro-inflammatory to anti-inflammatory macrophages (CD68/CD206) was noted in both groups.
CONCLUSIONS:
We found that the intramyocardial transplanted hUC-MSCs engrafted and partially transdifferentiated into cardiomyocytes, reduced scar formation, and induced angiogenesis through the association of pro/anti-inflammatory macrophages.
Copyright © 2020 Elsevier GmbH. All rights reserved.
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