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1.
Arch Toxicol ; 2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34657219

RESUMO

It has been nearly 15 years since the discovery of human-induced pluripotent stem cells (iPSCs). During this time, differentiation methods to targeted cells have dramatically improved, and many types of cells in the human body can be currently generated at high efficiency. In the cardiovascular field, the ability to generate human cardiomyocytes in vitro with the same genetic background as patients has provided a great opportunity to investigate human cardiovascular diseases at the cellular level to clarify the molecular mechanisms underlying the diseases and discover potential therapeutics. Additionally, iPSC-derived cardiomyocytes have provided a powerful platform to study drug-induced cardiotoxicity and identify patients at high risk for the cardiotoxicity; thus, accelerating personalized precision medicine. Moreover, iPSC-derived cardiomyocytes can be sources for cardiac cell therapy. Here, we review these achievements and discuss potential improvements for the future application of iPSC technology in cardiovascular diseases.

2.
Methods Mol Biol ; 2320: 3-7, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302642

RESUMO

The ability to differentiate pluripotent stem cells to cardiomyocyte lineages (PSC-CMs) has opened the door to new disease models and innovative drug and cell therapies for the heart. Nevertheless, further advances in the differentiation protocols are needed to fulfill the promise of PSC-CMs. Obstacles that remain include deriving PSC-CMs with proper electromechanical properties, coalescing them into functional tissue structures, and manipulating the genome to test the impact mutations have on arrhythmias and other heart disorders. This chapter gives a brief consideration of these challenges and outlines current methodologies that offer partial solutions.


Assuntos
Miócitos Cardíacos/citologia , Células-Tronco Pluripotentes/citologia , Diferenciação Celular/fisiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Cardiopatias/terapia , Humanos , Mutação/genética
3.
Methods Mol Biol ; 2320: 29-33, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302645

RESUMO

The human adult heart consists of approximately four billion cardiomyocytes, which do not possess self-renewal abilities. Severe myocardial infarction and dilated cardiomyopathy result in the loss of more than a billion cardiomyocytes. Induced pluripotent stem cells (iPSCs) can differentiate into various types of cells. Due to this ability, these cells could potentially serve as a new resource for cell therapy. Many studies have utilized cardiomyocytes derived from iPSCs for myocardial regeneration therapy. To obtain large number of cardiomyocytes for transplantation, we need to develop effective methods that would allow us to dissociate multiple cardiomyocyte aggregates simultaneously. Here, we describe a method to efficiently dissociate large number of iPSC-derived cardiomyocyte aggregates.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Infarto do Miocárdio/terapia
4.
Methods Mol Biol ; 2320: 35-51, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302646

RESUMO

The most common method for isolating cells of interest is an antibody method that recognizes cell surface antigens. However, specific surface antigens for many cell types have not been identified. We have developed the microRNA (miRNA)-responsive synthetic mRNA systems (miRNA switches), which isolate target cells based on endogenous miRNA activity. In this chapter, we describe protocols for isolating human pluripotent stem cell (hPSC)-derived cardiomyocytes using miRNA switches with or without cell sorting.


Assuntos
MicroRNAs/genética , Miócitos Cardíacos/citologia , Células-Tronco Pluripotentes/citologia , Técnicas de Cultura de Células/métodos , Diferenciação Celular/fisiologia , Linhagem Celular , Separação Celular/métodos , Citometria de Fluxo/métodos , Humanos , RNA Mensageiro/genética
5.
Methods Mol Biol ; 2320: 101-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302652

RESUMO

FluoVolt, a membrane potential dye, has been used to depict the action potentials of cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) in order to classify the cardiac cell subtype, evaluate long QT syndrome, and conduct cardiotoxic drug-responsive tests. To apply FluoVolt, users must prepare the hiPSC-CMs, assess the dye loadings, and apply the excitation light. Here we describe the steps to measure action potentials from single hiPSC-CMs and hiPSC-CM monolayers using this dye.


Assuntos
Potenciais de Ação/fisiologia , Diferenciação Celular/fisiologia , Corantes/química , Corpos Embrioides/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Células Cultivadas , Humanos , Síndrome do QT Longo/terapia
6.
Methods Mol Biol ; 2320: 135-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302655

RESUMO

Human iPSC-derived cardiomyocytes (hiPSC-CMs) are expected to be used in regenerative therapies and drug discovery for heart failure. hiPSC-CMs are a mixture of mainly ventricular CMs (VCMs) and also of atrial CMs (ACMs) and pacemaker cells. Here we describe a method to enrich VCM and ACM differentiation and to characterize these subtypes by gene expression analysis using qRT-PCR and by electrophysiological properties using the patch-clamp method. The differentiated VCMs and ACMs highly express VCM and ACM marker genes, respectively. Furthermore, both subtypes show specific properties of action potentials.


Assuntos
Ventrículos do Coração/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Potenciais de Ação/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Fenômenos Eletrofisiológicos/fisiologia , Átrios do Coração/citologia , Humanos , Técnicas de Patch-Clamp/métodos
7.
Methods Mol Biol ; 2320: 171-180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302658

RESUMO

Engineered cardiac tissue (ECT) derived from human induced pluripotent stem cells (iPSCs) can replicate human heart in vitro and be applied to drug discovery and heart disease models. The contraction force of ECT is an important indicator of its function and of the disease phenotype. Here we describe a construction method of ECT using the Flexcell® Tissue Train® culture system and a contraction force measurement method based on the Frank-Starling law.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Engenharia Tecidual/métodos , Células Cultivadas , Humanos
8.
Stem Cell Reports ; 16(8): 1906-1922, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34297940

RESUMO

Hand1 and Hand2 are transcriptional factors, and knockout mice of these genes show left and right ventricular hypoplasia, respectively. However, their function and expression in human cardiogenesis are not well studied. To delineate their expressions and assess their functions in human cardiomyocytes (CMs) in vitro, we established two triple-reporter human induced pluripotent stem cell lines that express HAND1mCherry, HAND2EGFP and either MYH6-driven iRFP670 or tagBFP constitutively and investigated their expression dynamics during cardiac differentiation. On day 5 of the differentiation, HAND1 expression marked cardiac progenitor cells. We profiled the CM subpopulations on day 20 with RNA sequencing and found that mCherry+ CMs showed higher proliferative ability than mCherry- CMs and identified a gene network of LEF1, HAND1, and HAND2 to regulate proliferation in CMs. Finally, we identified CD105 as a surface marker of highly proliferative CMs.

9.
Methods Mol Biol ; 2320: 219-232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302661

RESUMO

Differentiation protocols to direct cell fate decision from pluripotent stem cells to cardiac myocytes normally achieve high purity and quality of cells. Nonetheless, the highly specialized anatomy of the heart enables the possibility that acquisition of terminal somatic differentiation from pluripotency might imply heterogeneity of non-desire cell lineages. Directed cardiac differentiation empowers differentiation of pool of cells commonly reported to contain different proportions of ventricular, atrial, and nodal-like cells. RNA sequencing (RNA-Seq) allows a precise transcriptional profiling, ensuring a quality checking of the cell identity our protocol has derived as a main outcome. Here we describe a workflow methodology on how to adapt RNA sequencing analysis for integration into the R analysis pipeline in order to characterize chamber-specific gene signatures of the major cardiac lineages of myocytes in the heart.


Assuntos
Perfilação da Expressão Gênica , Átrios do Coração/citologia , Ventrículos do Coração/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/química , RNA-Seq/métodos , Transcriptoma , Diferenciação Celular/genética , Células Cultivadas , Análise por Conglomerados , Ontologia Genética , Átrios do Coração/química , Ventrículos do Coração/química , Humanos , Análise de Componente Principal , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Fluxo de Trabalho
10.
Methods Mol Biol ; 2320: 285-293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302665

RESUMO

Myocardial infarction is caused by a lack of oxygen due to blockage of a coronary artery and is a common cause of heart failure. Despite therapeutic advances, the prognosis of patients with heart failure is poor. One of the reasons is that present therapeutic approaches do not restore the loss of cardiac tissue. Stem cell-based therapies have the potential to regenerate the myocardium, and numerous studies using stem cells have shown improved cardiac function and reduced infarct size. In this chapter, we describe our methodology for transplanting human induced pluripotent stem cell-derived cardiomyocytes into immunodeficient mouse hearts with myocardial infarction.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/transplante , Animais , Modelos Animais de Doenças , Coração/fisiologia , Humanos , Injeções Intramusculares , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos NOD , Infarto do Miocárdio/terapia , Regeneração , Respiração Artificial/métodos , Respiração Artificial/veterinária , Toracotomia/métodos , Toracotomia/veterinária
11.
Methods Mol Biol ; 2320: 193-217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302660

RESUMO

RNA sequencing profiles and characterizes cell and tissue samples, giving important insights into molecular mechanisms. Such data is imperative for cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) and used in related translational and basic research. Here we provide reliable protocols to extract differentially expressed genes in iPSC-CMs with RNA sequencing.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/química , RNA-Seq/métodos , Transcriptoma , Diferenciação Celular/genética , Células Cultivadas , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Biblioteca Gênica , Genes Reporter , Genoma Humano , Humanos , MicroRNAs/genética , Análise de Componente Principal , RNA/isolamento & purificação , Alinhamento de Sequência , Software
12.
Nat Commun ; 12(1): 3596, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155205

RESUMO

One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1EmGFP and TNNI3mCherry double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Receptores de Estrogênio/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Receptores de Estrogênio/química , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Sarcolema/efeitos dos fármacos , Sarcolema/metabolismo , Sarcômeros/efeitos dos fármacos , Sarcômeros/metabolismo , Transcriptoma/efeitos dos fármacos , Troponina I/genética , Troponina I/metabolismo
13.
Stem Cell Reports ; 16(4): 883-898, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33798449

RESUMO

The transplantation of muscle progenitor cells (MuPCs) differentiated from human induced pluripotent stem cells (hiPSCs) is a promising approach for treating skeletal muscle diseases such as Duchenne muscular dystrophy (DMD). However, proper purification of the MuPCs before transplantation is essential for clinical application. Here, by using MYF5 hiPSC reporter lines, we identified two markers for myogenic cell purification: CDH13, which purified most of the myogenic cells, and FGFR4, which purified a subset of MuPCs. Cells purified with each of the markers showed high efficiency for regeneration after transplantation and contributed to the restoration of dystrophin expression in DMD-immunodeficient model mice. Moreover, we found that MYF5 regulates CDH13 expression by binding to the promoter regions. These findings suggest that FGFR4 and CDH13 are strong candidates for the purification of hiPSC-derived MuPCs for therapeutical application.

14.
Circ J ; 85(3): 323-329, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33518695

RESUMO

Due to the COVID-19 pandemic, the 84thAnnual Meeting of the Japanese Circulation Society (JCS) was held in a web-based format for the first time in its history as "The Week for JCS 2020" from Monday, July 27 to Sunday, August 2, 2020. All sessions, including general abstracts, were streamed live or on-demand. The main theme of the meeting was "Change Practice!" and the aim was to organize the latest findings in the field of cardiovascular medicine and discuss how to change practice. The total number of registered attendees was over 16,800, far exceeding our expectations, and many of the sessions were viewed by far more people than at conventional face-to-face scientific meetings. At this conference, the power of online information dissemination was fully demonstrated, and the evolution of online academic meetings will be a direction that cannot be reversed in the future. The meeting was completed with great success, and we express our heartfelt gratitude to all affiliates for their enormous amount of work, cooperation, and support.


Assuntos
Cardiologia/organização & administração , Congressos como Assunto/organização & administração , Sociedades Científicas/organização & administração , Telecomunicações/organização & administração , Cardiologia/tendências , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/terapia , Congressos como Assunto/estatística & dados numéricos , Congressos como Assunto/tendências , Humanos , Japão , Pesquisa , Inquéritos e Questionários , Telecomunicações/estatística & dados numéricos , Telecomunicações/tendências
15.
Haematologica ; 106(6): 1581-1590, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32439725

RESUMO

Leukocytes that lack HLA allelic expression are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy (IST), although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at position 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to 4 HLA supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P.

16.
PLoS One ; 15(11): e0241287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137106

RESUMO

Currently, cardiomyocyte (CM) differentiation methods require a purification step after CM induction to ensure the high purity of the cell population. Here we show an improved human CM differentiation protocol with which high-purity ventricular-type CMs can be obtained and maintained without any CM purification process. We induced and collected a mesodermal cell population (platelet-derived growth factor receptor-α (PDGFRα)-positive cells) that can respond to CM differentiation cues, and then stimulated CM differentiation by means of Wnt inhibition. This method reproducibly generated CMs with purities above 95% in several human pluripotent stem cell lines. Furthermore, these CM populations were maintained in culture at such high purity without any further CM purification step for over 200 days. The majority of these CMs (>95%) exhibited a ventricular-like phenotype with a tendency to structural and electrophysiological maturation, including T-tubule-like structure formation and the ability to respond to QT prolongation drugs. This is a simple and valuable method to stably generate CM populations suitable for cardiac toxicology testing, disease modeling and regenerative medicine.


Assuntos
Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Mesoderma/crescimento & desenvolvimento , Miócitos Cardíacos/citologia , Técnicas de Cultura de Células/métodos , Linhagem da Célula/genética , Fenômenos Eletrofisiológicos , Ventrículos do Coração/citologia , Humanos , Mesoderma/citologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Wnt/antagonistas & inibidores
17.
PLoS One ; 15(10): e0240129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33048975

RESUMO

AIMS: GJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function. METHODS AND RESULTS: We examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization. CONCLUSIONS: These results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.


Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Conexinas/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Adulto , Substituição de Aminoácidos , Angiotensina II/toxicidade , Animais , Animais Geneticamente Modificados , Células COS , Cardiomiopatia Hipertrófica Familiar/diagnóstico , Cardiomiopatia Hipertrófica Familiar/patologia , Cardiomiopatia Hipertrófica Familiar/cirurgia , Criança , Chlorocebus aethiops , Conexina 43/metabolismo , Conexinas/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Feminino , Junções Comunicantes/patologia , Técnicas de Inativação de Genes , Testes Genéticos , Transplante de Coração , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Camundongos , Infarto do Miocárdio/etiologia , Miocárdio/citologia , Miócitos Cardíacos , Linhagem , Cultura Primária de Células , Domínios Proteicos/genética , Ratos , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
18.
Front Cell Dev Biol ; 8: 761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903469

RESUMO

Background: Long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the SCN5A gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of ß-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that ß-blocker therapy reduced the risk of life-threatening cardiac events in female patients; however, the detailed mechanism of action remains unclear. Objectives: This study aimed to establish LQT3-human induced pluripotent stem cells (hiPSCs) and to investigate the effect of propranolol in this model. Method: An hiPSCs cell line was established from peripheral blood mononuclear cells of a boy with LQT3 carrying the SCN5A-N1774D mutation. He had suffered from repetitive torsades de pointes (TdPs) with QT prolongation since birth (QTc 680 ms), which were effectively treated with propranolol, as it suppressed lethal arrhythmias. Furthermore, hiPSCs were differentiated into cardiomyocytes (CMs), on which electrophysiological functional assays were performed using the patch-clamp method. Results: N1774D-hiPSC-CMs exhibited significantly prolonged action potential durations (APDs) in comparison to those of the control cells (N1774D: 440 ± 37 ms vs. control: 272 ± 22 ms; at 1 Hz pacing; p < 0.01). Furthermore, N1774D-hiPSC-CMs presented gain-of-function features: a hyperpolarized shift of steady-state activation and increased late sodium current compared to those of the control cells. 5 µM propranolol shortened APDs and inhibited late sodium current in N1774D-hiPSC-CMs, but did not significantly affect in the control cells. In addition, even in the presence of intrapipette guanosine diphosphate ßs (GDPßs), an inhibitor of G proteins, propranolol reduced late sodium current in N1774D cells. Therefore, these results suggested a unique inhibitory effect of propranolol on late sodium current unrelated to ß-adrenergic receptor block in N1774D-hiPSC-CMs. Conclusion: We successfully recapitulated the clinical phenotype of LQT3 using patient-derived hiPSC-CMs and determined that the mechanism, by which propranolol inhibited the late sodium current, was independent of ß-adrenergic receptor signaling pathway.

19.
Commun Biol ; 3(1): 434, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792557

RESUMO

Recent high-throughput approaches have revealed a vast number of transcripts with unknown functions. Many of these transcripts are long noncoding RNAs (lncRNAs), and intergenic region-derived lncRNAs are classified as long intergenic noncoding RNAs (lincRNAs). Although Myosin heavy chain 6 (Myh6) encoding primary contractile protein is down-regulated in stressed hearts, the underlying mechanisms are not fully clarified especially in terms of lincRNAs. Here, we screen upregulated lincRNAs in pressure overloaded hearts and identify a muscle-abundant lincRNA termed Lionheart. Compared with controls, deletion of the Lionheart in mice leads to decreased systolic function and a reduction in MYH6 protein levels following pressure overload. We reveal decreased MYH6 results from an interaction between Lionheart and Purine-rich element-binding protein A after pressure overload. Furthermore, human LIONHEART levels in left ventricular biopsy specimens positively correlate with cardiac systolic function. Our results demonstrate Lionheart plays a pivotal role in cardiac remodeling via regulation of MYH6.


Assuntos
Coração/fisiopatologia , Pressão , RNA Longo não Codificante/genética , Sístole/genética , Animais , Biópsia , Dependovirus/metabolismo , Ventrículos do Coração/ultraestrutura , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/metabolismo , Ratos , Regulação para Cima/genética
20.
Immunohorizons ; 4(7): 430-441, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680908

RESUMO

The loss of killer cell Ig-like receptor ligands (KIR-Ls) due to the copy number-neutral loss of heterozygosity of chromosome 6p (6pLOH) in leukocytes of patients with acquired aplastic anemia (AA) may alter the susceptibility of the affected leukocytes to NK cell killing in vivo. We studied 408 AA patients, including 261 who were heterozygous for KIR-Ls, namely C1/C2 or Bw6/Bw4, for the presence of KIR-L-missing [KIR-L(-)] leukocytes. KIR-L(-) leukocytes were found in 14 (5.4%, C1 [n = 4], C2 [n = 3], and Bw4 [n = 7]) of the 261 patients, in whom corresponding KIR(+) licensed NK cells were detected. The incidence of 6pLOH in the 261 patients (18.0%) was comparable to that in 147 patients (13.6%) who were homozygous for KIR-L genes. The percentages of HLA-lacking granulocytes (0.8-50.3%, median 15.2%) in the total granulocytes of the patients with KIR-L(-) cells were significantly lower than those (1.2-99.4%, median 55.4%) in patients without KIR-L(-) cells. KIR2DS1 and KIR3DS1 were only possessed by three of the 14 patients, two of whom had C2/C2 leukocytes after losing C1 alleles. The expression of the KIR3DS1 ligand HLA-F was selectively lost on KIR-L(-) primitive hematopoietic stem cells derived from 6pLOH(+) induced pluripotent stem cells in one of the KIR3DS1(+) patients. These findings suggest that human NK cells are able to suppress the expansion of KIR-L(-) leukocytes but are unable to eliminate them partly due to the lack of activating KIRs on NK cells and the low HLA-F expression level on hematopoietic stem cells in AA patients.

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