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Pubblicazioni recenti - cardiac fibroblast
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Cultured Cardiac Fibroblasts and Myofibroblasts Express Sushi Containing Domain 2 and Assemble a Unique Fibronectin Rich Matrix.
Exp Cell Res2021 Jan;():112489. doi: S0014-4827(21)00020-3.
Schmuck Eric G, Roy Sushmita, Dhillon Anisa, Walker Sydney, Spinali Keith, Colevas Sophia, Zhou Tianhua, Chhabra Gagan, Liu Yuming, Kader Sagar Md Abdul, Childs Charlie J, Kink John A, Eliceiri Kevin W, Hematti Peiman, Raval Amish N,
Abstract
Cardiac fibroblasts and myofibroblasts assemble and maintain extracellular matrix during normal development and following injury. Culture expansion of these cells yield a bioengineered matrix that could lead to intriguing therapeutic opportunities. For example, we reported that cultured rat cardiac fibroblasts form a matrix that can be used to delivery therapeutic stem cells. Furthermore, we reported that matrix derived from cultured human cardiac fibroblasts/myofibroblasts converted monocytes into macrophages that express interesting anti-inflammatory and pro-angiogenic properties. Expanding these matrix investigations require characterization of the source cells for quality control. In these efforts, we observed and herein report that Sushi Containing Domain 2 (SUSD2) is a novel and consistent marker for cultured human cardiac fibroblast and myofibroblasts.
Copyright © 2021. Published by Elsevier Inc.
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Cadherin-11 deficiency mitigates high-fat diet-induced inflammatory atrial remodeling and vulnerability to atrial fibrillation.
J Cell Physiol2021 Jan;():. doi: 10.1002/jcp.30257.
Fang Guojian, Cao Wei, Chen Long, Song Shuai, Li Yingze, Yuan Jiali, Fei Yudong, Ge Zhuowang, Chen Yuhan, Zhou Lei, Xiao Ying, Wan Yi, Wang Yuepeng, Wang Qunshan,
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin-11 (Cad-11), as a member of the cadherin family, can make a contribution to diet-induced obesity and it will be informative to know whether Cad-11 exerts its effects on atrial remodeling and AF vulnerability in a diet-induced obesity model. In this study, we demonstrated that the expression of Cad-11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high-fat diet (HFD) feeding. Further confirmed that Cad-11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad-11 mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad-11 mice. Mechanistically, Cad-11 activated mitogen-activated protein kinases and nuclear factor-?B for interleukin-6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity-related AF, suggesting Cad-11 might be a new therapeutic target for obesity-related AF.
© 2021 Wiley Periodicals LLC.
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PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia.
Sci Rep2021 Jan;11(1):1518. doi: 10.1038/s41598-021-81170-2.
Stafford Nicholas, Zi Min, Baudoin Florence, Mohamed Tamer M A, Prehar Sukhpal, De Giorgio Daria, Cartwright Elizabeth J, Latini Roberto, Neyses Ludwig, Oceandy Delvac,
Abstract
Ischaemic heart disease is the world's leading cause of mortality. Survival rates from acute myocardial infarction (MI) have improved in recent years; however, this has led to an increase in the prevalence of heart failure (HF) due to chronic remodelling of the infarcted myocardium, for which treatment options remain poor. We have previously shown that inhibition of isoform 4 of the plasma membrane calcium ATPase (PMCA4) prevents chronic remodelling and HF development during pressure overload, through fibroblast mediated Wnt signalling modulation. Given that Wnt signalling also plays a prominent role during remodelling of the infarcted heart, this study investigated the effect of genetic and functional loss of PMCA4 on cardiac outcomes following MI. Neither genetic deletion nor pharmacological inhibition of PMCA4 affected chronic remodelling of the post-MI myocardium. This was the case when PMCA4 was deleted globally, or specifically from cardiomyocytes or fibroblasts. PMCA4-ablated hearts were however less prone to acute arrhythmic events, which may offer a slight survival benefit. Overall, this study demonstrates that PMCA4 inhibition does not affect chronic outcomes following MI.
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In Situ "Humanization" of Porcine Bioprostheses: Demonstration of Tendon Bioprostheses Conversion into Human ACL and Possible Implications for Heart Valve Bioprostheses.
Bioengineering (Basel)2021 Jan;8(1):. doi: E10.
Galili Uri, Stone Kevin R,
Abstract
This review describes the first studies on successful conversion of porcine soft-tissue bioprostheses into viable permanently functional tissue in humans. This process includes gradual degradation of the porcine tissue, with concomitant neo-vascularization and reconstruction of the implanted bioprosthesis with human cells and extracellular matrix. Such a reconstruction process is referred to in this review as "humanization". Humanization was achieved with porcine bone-patellar-tendon-bone (BTB), replacing torn anterior-cruciate-ligament (ACL) in patients. In addition to its possible use in orthopedic surgery, it is suggested that this humanization method should be studied as a possible mechanism for converting implanted porcine bioprosthetic heart-valves (BHV) into viable tissue valves in young patients. Presently, these patients are only implanted with mechanical heart-valves, which require constant anticoagulation therapy. The processing of porcine bioprostheses, which enables humanization, includes elimination of ?-gal epitopes and partial (incomplete) crosslinking with glutaraldehyde. Studies on implantation of porcine BTB bioprostheses indicated that enzymatic elimination of ?-gal epitopes prevents subsequent accelerated destruction of implanted tissues by the natural anti-Gal antibody, whereas the partial crosslinking by glutaraldehyde molecules results in their function as "speed bumps" that slow the infiltration of macrophages. Anti-non gal antibodies produced against porcine antigens in implanted bioprostheses recruit macrophages, which infiltrate at a pace that enables slow degradation of the porcine tissue, neo-vascularization, and infiltration of fibroblasts. These fibroblasts align with the porcine collagen-fibers scaffold, secrete their collagen-fibers and other extracellular-matrix (ECM) components, and gradually replace porcine tissues degraded by macrophages with autologous functional viable tissue. Porcine BTB implanted in patients completes humanization into autologous ACL within ~2 years. The similarities in cells and ECM comprising heart-valves and tendons, raises the possibility that porcine BHV undergoing a similar processing, may also undergo humanization, resulting in formation of an autologous, viable, permanently functional, non-calcifying heart-valves.
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The FGF-AKT pathway is necessary for cardiomyocyte survival for heart regeneration in zebrafish.
Dev Biol2021 Jan;():. doi: S0012-1606(21)00003-8.
Tahara Naoyuki, Akiyama Ryutaro, Wang Justin, Kawakami Hiroko, Bessho Yasumasa, Kawakami Yasuhiko,
Abstract
Zebrafish have a remarkable ability to regenerate the myocardium after injury by proliferation of pre-existing cardiomyocytes. Fibroblast growth factor (FGF) signaling is known to play a critical role in zebrafish heart regeneration through promotion of neovascularization of the regenerating myocardium. Here, we define an additional function of FGF signaling in the zebrafish myocardium after injury. We find that FGF signaling is active in a small fraction of cardiomyocytes before injury, and that the number of FGF signaling-positive cardiomyocytes increases after amputation-induced injury. We show that ERK phosphorylation is prominent in endothelial cells, but not in cardiomyocytes. In contrast, basal levels of phospho-AKT positive cardiomyocytes are detected before injury, and the ratio of phosphorylated AKT-positive cardiomyocytes increases after injury, indicating a role of AKT signaling in cardiomyocytes following injury. Inhibition of FGF signaling reduced the number of phosphorylated AKT-positive cardiomyocytes and increased cardiomyocyte death without injury. Heart injury did not induce cardiomyocyte death; however, heart injury in combination with inhibition of FGF signaling caused significant increase in cardiomyocyte death. Pharmacological inhibition of AKT signaling after heart injury also caused increased cardiomyocyte death. Our data support the idea that FGF-AKT signaling-dependent cardiomyocyte survival is necessary for subsequent heart regeneration.
Copyright © 2021. Published by Elsevier Inc.
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Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly.
Genet Med2021 Jan;():. doi: 10.1038/s41436-020-01052-2.
Horn Denise, Fernández-Núñez Elisa, Gomez-Carmona Ricardo, Rivera-Barahona Ana, Nevado Julian, Schwartzmann Sarina, Ehmke Nadja, Lapunzina Pablo, Otaify Ghada A, Temtamy Samia, Aglan Mona, Boschann Felix, Ruiz-Perez Victor L,
Abstract
PURPOSE:
This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families.
METHODS:
Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays.
RESULTS:
A clinically recognizable syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.
CONCLUSION:
Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development.
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Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.
PLoS Med2021 Jan;18(1):e1003513. doi: 10.1371/journal.pmed.1003513.
Wallentin Lars, Eriksson Niclas, Olszowka Maciej, Grammer Tanja B, Hagström Emil, Held Claes, Kleber Marcus E, Koenig Wolfgang, März Winfried, Stewart Ralph A H, White Harvey D, Åberg Mikael, Siegbahn Agneta,
Abstract
BACKGROUND:
Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.
METHODS AND FINDINGS:
The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapladIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973) carried most prognostic information. The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.
CONCLUSIONS:
Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT00799903.
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ATF3 expression in cardiomyocytes and myofibroblasts following transverse aortic constriction displays distinct phenotypes.
Int J Cardiol Heart Vasc2021 Feb;32():100706. doi: 10.1016/j.ijcha.2020.100706.
Soraya Abu-Sharki, Tali Haas, Rona Shofti, Tom Friedman, Roy Kalfon, Ami Aronheim,
Abstract
Background:
Activating transcription 3 (ATF3) is a member of the basic leucine zipper family of transcription factors. ATF3 is an immediate early gene expressed following various cellular stresses. ATF3 acts through binding to cyclic AMP response elements found in the promoters of key regulatory proteins that determine cell fate. In the heart, multiple cardiac stresses result in chronic ATF3 expression. Transgenic mice with ATF3 expression in cardiomyocytes clearly demonstrate that ATF3 serves a leading role in heart hypertrophy, cardiac fibrosis, cardiac dysfunction and death. In contrast, the use of ATF3 whole body knockout mice resulted non-conclusive results. The heart is composed of various cell types such as cardiomyocytes, fibroblasts, endothelial and immune cells. The question that we addressed in this study is whether ablation of ATF3 in unique cell types in the heart results in diverse cardiac phenotypes.
Methods:
ATF3-flox mice were crossed with ?MHC and Postn specific promoters directing CRE expression and thus ATF3 ablation in cardiomyocytes and myofibroblast cells. Mice were challenged with transverse aortic constriction (TAC) for eight weeks and heart function, ventricle weight, hypertrophic markers, fibrosis markers and ATF3 expression were assessed by qRT-PCR.
Results:
The results of the study show that ATF3 deletion in cardiomyocytes followed by TAC resulted in reduced heart growth and dampened fibrosis response while ATF3 ablation in myofibroblasts displayed a reduced hypertrophic gene program.
Conclusions:
TAC-operation results in increased ATF3 expression in both myofibroblasts and cardiomyocytes that promotes a hypertrophic program and fibrotic cardiac growth, respectively.
© 2020 The Authors.
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Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome.
Sci Rep2021 Jan;11(1):690. doi: 10.1038/s41598-020-80086-7.
Pekkarinen Pirkka T, Skrifvars Markus B, Lievonen Ville, Jakkula Pekka, Albrecht Laura, Loisa Pekka, Tiainen Marjaana, Pettilä Ville, Reinikainen Matti, Hästbacka Johanna,
Abstract
Fibroblast growth factor (FGF) 21 is a marker associated with mitochondrial and cellular stress. Cardiac arrest causes mitochondrial stress, and we tested if FGF 21 would reflect the severity of hypoxia-reperfusion injury after cardiac arrest. We measured serum concentrations of FGF 21 in 112 patients on ICU admission and 24, 48 and 72 h after out-of-hospital cardiac arrest with shockable initial rhythm included in the COMACARE study (NCT02698917). All patients received targeted temperature management for 24 h. We defined 6-month cerebral performance category 1-2 as good and 3-5 as poor neurological outcome. We used samples from 40 non-critically ill emergency room patients as controls. We assessed group differences with the Mann Whitney U test and temporal differences with linear modeling with restricted maximum likelihood estimation. We used multivariate logistic regression to assess the independent predictive value of FGF 21 concentration for neurologic outcome. The median (inter-quartile range, IQR) FGF 21 concentration was 0.25 (0.094-0.91) ng/ml in controls, 0.79 (0.37-1.6) ng/ml in patients at ICU admission (P?
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Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset PD patient fibroblasts.
Mol Ther Methods Clin Dev2021 Mar;20():227-236. doi: 10.1016/j.omtm.2020.11.011.
Buratti Emanuele, Peruzzo Paolo, Braga Luca, Zanin Irene, Stuani Cristiana, Goina Elisa, Romano Maurizio, Giacca Mauro, Dardis Andrea,
Abstract
Pompe disease (PD) is an autosomal recessive lysosomal storage disorder due to deficient activity of the acid alpha glucosidase enzyme (GAA). As a consequence of the enzymatic defect, undigested glycogen accumulates within lysosomes. Most patients affected by the late-onset (LO) phenotype carry in at least one allele the c.-32-13T>G variant, which leads to exon 2 exclusion from the pre-mRNA. These patients display a variable and suboptimal response to enzyme replacement therapy. To identify novel therapeutic approaches, we developed a fluorescent GAA exon 2 splicing assay and screened a library of US Food and Drug Administration (FDA)-approved compounds. This led to the identification of several drugs able to restore normal splicing. Among these, we further validated the effects of the iron chelator deferoxamine (Defe) in c.-32-13T>G fibroblasts. Defe treatment resulted in a 2-fold increase of GAA exon 2 inclusion and a 40% increase in enzymatic activity. Preliminary results suggest that this effect is mediated by the regulation of iron availability, at least partially. RNA-seq experiments also showed that Defe might shift the balance of splicing factor levels toward a profile promoting GAA exon 2 inclusion. This work provides the basis for drug repurposing and development of new chemically modified molecules aimed at improving the clinical outcome in LO-PD patients.
© 2020 The Authors.
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Mechanical and Physical Regulation of Fibroblast-Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology.
Front Bioeng Biotechnol2020 ;8():609653. doi: 10.3389/fbioe.2020.609653.
D'Urso Mirko, Kurniawan Nicholas A,
Abstract
Fibroblasts are cells present throughout the human body that are primarily responsible for the production and maintenance of the extracellular matrix (ECM) within the tissues. They have the capability to modify the mechanical properties of the ECM within the tissue and transition into myofibroblasts, a cell type that is associated with the development of fibrotic tissue through an acute increase of cell density and protein deposition. This transition from fibroblast to myofibroblast-a well-known cellular hallmark of the pathological state of tissues-and the environmental stimuli that can induce this transition have received a lot of attention, for example in the contexts of asthma and cardiac fibrosis. Recent efforts in understanding how cells sense their physical environment at the micro- and nano-scales have ushered in a new appreciation that the substrates on which the cells adhere provide not only passive influence, but also active stimulus that can affect fibroblast activation. These studies suggest that mechanical interactions at the cell-substrate interface play a key role in regulating this phenotype transition by changing the mechanical and morphological properties of the cells. Here, we briefly summarize the reported chemical and physical cues regulating fibroblast phenotype. We then argue that a better understanding of how cells mechanically interact with the substrate (mechanosensing) and how this influences cell behaviors (mechanotransduction) using well-defined platforms that decouple the physical stimuli from the chemical ones can provide a powerful tool to control the balance between physiological tissue regeneration and pathological fibrotic response.
Copyright © 2020 D'Urso and Kurniawan.
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Inflamed ulcerative colitis regions associated to MRGPRX2-mediated mast cell degranulation and cell activation modules, defining a new therapeutic target.
Gastroenterology2021 Jan;():. doi: S0016-5085(21)00024-X.
Chen Ernie, Chuang Ling-Shiang, Giri Mamta, Villaverde Nicole, Hsu Nai-Yun, Sabic Ksenija, Joshowitz Sari, Gettler Kyle, Nayar Shikha, Chai Zhi, Alter Isaac L, Chasteau Colleen C, Korie Ujunwa M, Dzedzik Siarhei, Thin Tin Htwe, Jain Aayushee, Moscati Arden, Bongers Gerardus, Duerr Richard H, Silverberg Mark S, Brant Steven R, Rioux John D, Peter Inga, Schumm L Philip, Haritunians Talin, McGovern Dermot P, Itan Yuval, Cho Judy H,
Abstract
BACKGROUND & AIMS:
Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well-established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC.
METHODS:
Colon tissues were collected from UC patients for bulk RNAseq and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing (scRNAseq). Genetic association of all protein altering GPCR SNPs was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into CHO and HMC-1.1 cells to detect genotype-dependent effects on ?-arrestin recruitment, IP-1 accumulation, and phosphoERK.
RESULTS:
Mast cell-specific mediators and ADM (adrenomedullin, proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are upregulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated, bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances beta-arrestin recruitment, decreases IP-1, and increases phosphoERK with MRGPRX2 agonists. scRNASeq defines that ADM is expressed by activated fibroblasts and epithelial cells, and that IFNG is a key, upstream regulator of mast cell gene expression.
CONCLUSION:
Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.
Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Autoimmune Congenital Heart Block: A Review of Biomarkers and Management of Pregnancy.
Front Pediatr2020 ;8():607515. doi: 10.3389/fped.2020.607515.
De Carolis Sara, Garufi Cristina, Garufi Ester, De Carolis Maria Pia, Botta Angela, Tabacco Sara, Salvi Silvia,
Abstract
Autoimmune Congenital Heart Block (CHB) is an immune-mediated disease due to transplacental passage of circulating anti-Ro/SSA and anti-La/SSB autoantibodies. It occurs in 2% of anti-Ro/SSA-exposed pregnancies, and recurrence rate is nine times higher in subsequent pregnancies. Aim of this review is to identify biomarkers of CHB and treatment strategies. The Ro-system is constituted by two polypeptides targeted by the anti-Ro52 and anti-Ro60 autoantibodies. The central portion of Ro52 (p200), more than the full amino-acid sequence of Ro-52, is recognized to be the fine specificity of anti-Ro associated to the highest risk of cardiac damage. If anti-p200 antibody should be tested, as biomarker of CHB, over standard commercial ELISAs is still debated. Recent studies indicate that type I-Interferon (IFN) can activate fibroblasts in fetal heart. In the mother the anti-Ro/La antibodies activate the type I IFN-signature, and maternal IFN-regulated genes correlate with a similar neonatal IFN-gene expression. Evaluation of maternal IFN-signature could be used as novel biomarker of CHB. The measurement of "mechanical" PR interval with weekly fetal echocardiogram (ECHO) from 16 to at least 24 weeks of gestation is strongly recommended for CHB prenatal diagnosis. However, ECHO screening presents some limitations due to difficult identification of first-degree block and possible occurrence of a complete block from a normal rhythm in few days. Maternal administration of Hydroxychloroquine from the tenth week of gestation, modulating toll-like receptor and autoantibody-dependent type I IFN activation on the fetus, has an important role in preventing CHB in pregnant women with high risk for recurrent CHB.
Copyright © 2020 De Carolis, Garufi, Garufi, De Carolis, Botta, Tabacco and Salvi.
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Generation of transgene-free induced pluripotent stem cells from cardiac fibroblasts of goat embryos.
J Stem Cells Regen Med2020 ;16(2):34-43. doi: 10.46582/jsrm.1602007.
Hanna Mira, Sahito Raja Ghazanfar Ali, Rateb Moshira, Kachiwal Allah Bux, Seddiek Hanan A, Bhutto Bachal, Hescheler Jürgen,
Abstract
Induced pluripotent stem cells (iPSCs) hold a great potential for therapeutic regenerative medicine. The aim of this study was to generate induced pluripotent stem cells from goat embryonic cardiac tissue derived fibroblasts. The isolated cardiac fibroblasts from the cardiac tissue of goat embryos were positive for alfa smooth muscle actin, vimentin and discoidin domain receptor2. From these cells, we generated transgene free iPSCs using piggyBac transposons / transposase using five transcription factors (Oct4, Sox2, Klf, Myc and Lin 28). The generated iPSCs were SSEA1, SSEA4 and Oct4 positive. They were cultured on neofeeders using 20% Serum replacement - IMDM with bFGF. They could form cystic and compact embryoid bodies that showed differentiated ectodermal and mesodermal like cells when cultured using 20% FBS-IMDM without bFGF. The iPSCs, generated in the frame of this approach were produced without the use of integrating virus and the reprogramming transgenes were removed at the end of the process. Though there were limitations in the approach used, a substantial sign of reprogramming was obtained.
Copyright © Journal of Stem Cells and Regenerative Medicine.
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Myocardial repair of bioengineered cardiac patches with decellularized placental scaffold and human-induced pluripotent stem cells in a rat model of myocardial infarction.
Stem Cell Res Ther2021 Jan;12(1):13. doi: 10.1186/s13287-020-02066-y.
Jiang Yu, Sun Si-Jia, Zhen Zhe, Wei Rui, Zhang Nannan, Liao Song-Yan, Tse Hung-Fat,
Abstract
BACKGROUND:
The creation of a bioengineered cardiac patch (BCP) is a potential novel strategy for myocardial repair. Nevertheless, the ideal scaffold for BCP is unknown.
OBJECTIVE:
We investigated whether the decellularized placenta (DP) could serve as natural scaffold material to create a BCP for myocardial repair.
METHODS AND RESULTS:
A BCP was created by seeding human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs; 1?×?106/cm2) onto DP. The functional and electrophysiological properties of the BCP were first characterized by in vitro analysis and optical mapping. Next, in vivo therapeutic efficacy of the BCP was evaluated in a rat model of myocardial infarction (MI), created by left descending coronary artery ligation (MI?+?BCP group), and compared with MI alone (MI group), transplantation of DP (MI?+?DP group), and hiPSC-CMs (MI?+?CM group). Cytokine profiling demonstrated that the BCP contained multiple growth and angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, basic fibroblast growth factor, angiogenin, and angiopoietin-2. In vitro optical mapping showed that the BCP exhibited organized mechanical contraction and synchronized electrical propagation. RNA sequencing showed that DP enhanced the maturation of hiPSC-CMs compared with the monolayer of cultured hiPSC-CMs. At 4?weeks follow-up, the BCP significantly improved left ventricular (LV) function, as determined by LV ejection fraction, fractional shortening, +?dP/dt, and end-systolic pressure-volume relationship, compared with the MI, MI?+?DP, and MI?+?CM groups. Moreover, histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI?+?DP, and MI?+?CM groups.
CONCLUSIONS:
Our results demonstrate that a DP scaffold contains multiple growth and angiogenic factors that enhance the maturation and survival of seeded hiPSC-CMs. Transplantation of a BCP is superior to DP or hiPSC-CMs alone in reducing infarct size and improving cell retention and neovascularization, thus providing a novel therapy for myocardial repair following MI.
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Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring.
Stem Cell Res Ther2021 Jan;12(1):23. doi: 10.1186/s13287-020-02061-3.
Zhang Chaoyu, Wang Ting, Zhang Li, Chen Penghong, Tang Shijie, Chen Aizhen, Li Ming, Peng Guohao, Gao Hangqi, Weng Haiyan, Zhang Haoruo, Li Shirong, Chen Jinghua, Chen Liangwan, Chen Xiaosong,
Abstract
BACKGROUND:
Mesenchymal stem cell-based acellular therapies have been widely exploited in managing hypertrophic scars. However, low maintenance dose and transitory therapeutic effects during topical medication remain a thorny issue. Herein, this study aimed to optimize the curative effect of adipose-derived stem cell conditioned medium (ADSC-CM) in the prevention of hypertrophic scarring.
METHODS:
In the present study, ADSC-CM was concentrated via the freeze-drying procedure. The efficacy of different dose groups (CM, CM5, CM10) was conducted on the proliferation, apoptosis, and ?-smooth muscle actin (?-SMA) expression of human keloid fibroblasts (HKFs) in vitro. Incorporation of adipose-derived stem cell concentrated conditioned medium (ADSCC-CM) into polysaccharide hydrogel was investigated in rabbit ear, in vivo. Haematoxylin-eosin (H&E) and Masson's trichrome staining were performed for the evaluation of scar hyperplasia.
RESULTS:
We noted that ADSCC-CM could downregulate the ?-SMA expression of HKFs in a dose-dependent manner. In the rabbit ear model, the scar hyperplasia in the medium-dose group (CM5) and high-dose group (CM10) was inhibited with reduced scar elevation index (SEI) under 4?months of observation. It is noteworthy that the union of CM5 and polysaccharide hydrogel (CM5+H) yielded the best preventive effect on scar hyperplasia. Briefly, melanin, height, vascularity, and pliability in the CM5+H group were better than those of the control group. Collagen was evenly distributed, and skin appendages could be regenerated.
CONCLUSIONS:
Altogether, ADSCC-CM can downregulate the expression of ?-SMA due to its anti-fibrosis effect and promote the rearrangement of collagen fibres, which is integral to scar precaution. The in situ cross bonding of ADSCC-CM and polysaccharide hydrogel could remarkably enhance the therapeutic outcomes in inhibiting scar proliferation. Hence, the alliance of ADSCC-CM and hydrogel may become a potential alternative in hypertrophic scar prophylaxis.
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FGF-23 correlates with endocrine and metabolism dysregulation, worse cardiac and renal function, inflammation level, stenosis degree, and independently predicts in-stent restenosis risk in coronary heart disease patients underwent drug-eluting-stent PCI.
BMC Cardiovasc Disord2021 Jan;21(1):24. doi: 10.1186/s12872-020-01839-w.
Song Tingting, Fu Yang, Wang Yanbo, Li Wei, Zhao Jiayu, Wang Xun, Wang Haiyan, Zhao Ying, Fu Xianghua,
Abstract
BACKGROUND:
The present study aimed to assess the correlation of fibroblast growth factor (FGF)-23 expression with clinical characteristics, then further explore its value in predicting 2-year in-stent restenosis (ISR) risk in coronary heart disease (CHD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stent (DES).
METHODS:
In this prospective, single-center, observational study, totally 214 CHD patients treated by PCI with DES were consecutively recruited, and peripheral blood samples were collected prior to PCI with DES for serum samples isolation. Following, FGF-23 level in the serum samples was detected via enzyme linked-immuno-sorbent Assay. The follow-up coronary angiography was performed at 1 year and 2 years after PCI or if suspected ISR symptoms occurred.
RESULTS:
FGF-23 was positively correlated with fasting blood-glucose, insulin resistance, serum creatinine, serum uric acid, LDL-C, high-sensitivity C-reactive protein, cardiac troponin I and N-terminal-proB-type natriuretic peptide, while was negatively associated with HDL-C and left ventricular ejection fraction (all P??0.05). Moreover, FGF-23 level was higher in 2-year ISR patients (n?=?38) compared to 2-year non-ISR patients (n?=?176) (P?
CONCLUSION:
FGF-23 correlates with endocrine and metabolism dysregulation, worse cardiac and renal function, inflammation level, stenosis degree of target lesion, and serves as an independent risk factor for 2-year ISR risk in CHD patients underwent PCI with DES.
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Action potential propagation and block in a model of atrial tissue with myocyte-fibroblast coupling.
Math Med Biol2021 Jan;():. doi: dqaa014.
Mortensen Peter, Gao Hao, Smith Godfrey, Simitev Radostin D,
Abstract
The electrical coupling between myocytes and fibroblasts and the spacial distribution of fibroblasts within myocardial tissues are significant factors in triggering and sustaining cardiac arrhythmias, but their roles are poorly understood. This article describes both direct numerical simulations and an asymptotic theory of propagation and block of electrical excitation in a model of atrial tissue with myocyte-fibroblast coupling. In particular, three idealized fibroblast distributions are introduced: uniform distribution, fibroblast barrier and myocyte strait-all believed to be constituent blocks of realistic fibroblast distributions. Primary action potential biomarkers including conduction velocity, peak potential and triangulation index are estimated from direct simulations in all cases. Propagation block is found to occur at certain critical values of the parameters defining each idealized fibroblast distribution, and these critical values are accurately determined. An asymptotic theory proposed earlier is extended and applied to the case of a uniform fibroblast distribution. Biomarker values are obtained from hybrid analytical-numerical solutions of coupled fast-time and slow-time periodic boundary value problems and compare well to direct numerical simulations. The boundary of absolute refractoriness is determined solely by the fast-time problem and is found to depend on the values of the myocyte potential and on the slow inactivation variable of the sodium current ahead of the propagating pulse. In turn, these quantities are estimated from the slow-time problem using a regular perturbation expansion to find the steady state of the coupled myocyte-fibroblast kinetics. The asymptotic theory gives a simple analytical expression that captures with remarkable accuracy the block of propagation in the presence of fibroblasts.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.
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Circulating exosomes in cardiovascular disease: Novel carriers of biological information.
Biomed Pharmacother2021 Jan;135():111148. doi: S0753-3322(20)31341-X.
Liu Qing, Piao Hulin, Wang Yong, Zheng Dongdong, Wang Weitie,
Abstract
Exosomes are a group of nanosized extracellular vesicles that include various bioactive nucleic acids, lipids, and proteins. They originate from membrane invagination and are released by exocytosis, which can transmit signals to target cells to achieve cell-to-cell communication and maintain homeostasis. The heart is a complex multicellular organ that contains resident cell types such as fibroblasts, endothelial cells, and smooth muscle cells. Communication between different cell types and immune systems is essential for the dynamic equilibrium of the cardiac internal environment. Intercellular communication is a universal phenomenon mediated by exosomes and their contents during several pathological processes in cardiovascular diseases, such as cardiomyocyte hypertrophy, apoptosis, and angiogenesis. Therefore, exosomes can be used as novel invasive diagnostic biomarkers in multiple diseases, including atherosclerosis, myocardial ischemia, cardiac fibrosis, and ischemia-reperfusion injury. In addition, the biocompatible nature and low immunogenicity of exosomes make them high-quality nanoparticle drug carriers with potential applications in translational medicine and therapeutic strategies. Here, we focus on the biogenesis, isolation, biological functions, and future application prospects of exosomes in cardiovascular disease.
Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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Multiscale Strategy to Resolve Stroma-Cardiac Fibroblast Interactions.
Circ Res2021 Jan;128(1):39-41. doi: 10.1161/CIRCRESAHA.120.318494.
Zimmermann Wolfram-Hubertus,
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