Kaomei Guan

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Verified

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• Dr. rer. nat.
• Professor at TUD Dresden University of Technology

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an important resource for the identification of new therapeutic targets and cardioprotective drugs. After differentiation iPSC-CMs show an immature, fetal-like phenotype. Cultivation of iPSC-CMs in lipid-supplemented maturation medium (MM) strongly enhances their structural,...

The immaturity of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a major limitation for their use in drug screening to identify pro-arrhythmogenic or cardiotoxic molecules. Here, we demonstrate an approach that combines lipid-enriched maturation medium with a high concentration of calcium, nanopatterning of culture surface...

Background and aim Mutations in the splice regulator RBM20 account for ∼3 % of genetic cardiomyopathies. In particular, the highly conserved RS domain is a hotspot for disease-associated mutations. Previously, mutations at same amino acid position 634 in the hotspot RS-domain were found to cause dilated cardiomyopathy (DCM) with left ventricular no...

Background Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long‐term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross‐sectional studies. We analyzed ADMA, SDMA, and other L‐arginine m...

Background: Cytoskeletal non-muscle actin isoforms are the most abundant intracellular proteins and extensively interact with other molecules. Biological consequences and genotype-phenotype correlations of the variants in genes encoding these isoforms, ACTB and ACTG1, are not delineated. Methods: Clinical data analysis from 290 individuals with pat...

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 Framework Programme (H2020) under Grant agreements No. 953138 (EMAPS-Cardio) Purpose Cardiotoxicity is one of the main side effects limiting development of new medicines and resulting in withdrawal of drugs from the market. There...

Aims Gene therapy with cardiac phosphodiesterases (PDEs) such as PDE4B has recently been described to effectively prevent heart failure in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here we studied whether g...

The immaturity of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a major limitation for their use in drug screening to identify pro-arrhythmogenic or cardiotoxic molecules, thus hindering their potential role in guiding personalised drug selection for patients. Here, we demonstrate an approach that combines lipid-enriched...

Background and Purpose The metalloprotease ADAM10 has been implicated in immune regulatory processes, is upregulated in response to specific heart pathologies e.g. ischemic heart failure, and elevated serum levels of the ADAM10 substrates CX3CL1 and CXCL16 have been reported following infarction. The causal role of ADAM10 in cardiovascular diseases...

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1‐7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro‐X carboxypeptidase that is able to cleave angioten...

Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical utility of myocardial epigenomics remains narrow owing to limited clinical access to tissue. Therefore, the current study determined...

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothes...

After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM...

Pathogenic ACTB and ACTG1 gene variants, encoding the actin isoforms βCYA and γCYA, respectively, are frequently associated with the Baraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) that includes malformations of cortical development. Here we explore whether cerebral organoids grown from BWCFF-S patient-derived induced pluripotent stem cells...

The combination of the human induced pluripotent stem cell (hiPSC) and organoid technology enables the generation of human 3D culture systems, providing the opportunity to model human tissue-like structures in vitro. This protocol offers the details to generate and characterize self-assembling 3D cardiac organoids in a controlled and efficient mann...

Calpains are calcium-activated neutral proteases involved in the regulation of key signaling pathways. Junctophilin-2 (JP2) is a Calpain-specific proteolytic target and essential structural protein inside Ca2+ release units required for excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in heart failu...

One of the major goals in cardiac regeneration research is to replace lost ventricular tissue with new cardiomyocytes. However, cardiomyocyte proliferation drops to low levels in neonatal hearts and is no longer efficient in compensating for the loss of functional myocardium in heart disease. We generated a human induced pluripotent stem cell (iPSC...

The potential of human induced pluripotent stem cells (iPSCs) to self-renew indefinitely and to differentiate virtually into any cell type in unlimited quantities makes them attractive for in-vitro disease modeling, drug screening, personalized medicine, and regenerative therapies. As the genome of iPSCs thoroughly reproduces that of the somatic ce...

Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activ...

Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to...

One of the major goals in cardiac regeneration research is to replace lost ventricular tissue with new cardiomyocytes. However, cardiomyocyte proliferation drops to low levels in neonatal hearts and is no longer efficient in compensating for the loss of functional myocardium in heart disease. We generated a human induced pluripotent stem cell (iPSC...

Recently, there have been great advances in cardiovascular channelopathy modeling and drug safety pharma-cology using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The automated patch-clamp (APC) technique overcomes the disadvantages of the manual patch-clamp (MPC) technique, which is labor intensive and gives low output. H...

Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways towards effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between polo-like kinase 2 (PLK2) an...

Despite known adverse effects of hydroxychloroquine (HCQ) and azithromycin (AZM) on cardiac function, HCQ and AZM have been used as combination therapy in the treatment of COVID-19 patients. Recent clinical data indicate higher complication rates with HCQ/AZM combination treatment in comparison to monotherapy. Here, we used human induced pluripoten...

Rationale: Loss-of-function of the cardiac sodium channel NaV1.5 causes conduction slowing and arrhythmias. NaV1.5 is differentially distributed within subcellular domains of cardiomyocytes, with sodium current (INa) being enriched at the intercalated discs (ID). Various pathophysiological conditions associated with lethal arrhythmias display ID-sp...

Recently, there have been great advances in cardiovascular channelopathy modeling and drug safety pharmacology using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The automated patch-clamp (APC) technique overcomes the disadvantages of manual patch-clamp (MPC) such as labor intensive and low output. However, it was not clea...

The increase in activity of the two-pore potassium-leak channel Kcnk5b maintains allometric juvenile growth of adult zebrafish appendages. However, it remains unknown how this channel maintains allometric growth and how its bioelectric activity is regulated to scale these anatomical structures. We show the activation of Kcnk5b is sufficient to acti...

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Resear...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inheritable cardiac disorder, which is characterized by life-threatening cardiac arrhythmias, syncope, seizures, or sudden cardiac death in response to physical exercise or emotional stress. This inherited disease is predominantly caused by mutations in the ryanodine receptor...

Patients with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD), an enzyme that is involved in the mitochondrial beta-oxidation of long-chain fatty acids, are at risk for developing cardiac arrhythmias. In human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), VLCAD deficiency (VLCADD) results in a series of abnormalit...

Background and purpose Following myocardial infarction (MI), adverse fibrotic remodeling with extensive deposition of extracellular matrix (ECM) components has substantial consequences for the contractility of the ventricle finally leading to terminal heart failure (HF). Recently, inhibition of ECM-remodeling enzymes is discussed as potential treat...

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygo...

Metabolic diseases and diabetes represent an increasing global challenge for human health care. As associated with a strongly elevated risk of developing atherosclerosis, kidney failure and death from myocardial infarction or stroke, the treatment of diabetes requires a more effective approach than lowering blood glucose levels. This review summari...

In adult cardiomyocytes (CMs), the type 2 ryanodine receptor (RYR2) is an indispensable Ca²⁺ release channel that ensures the integrity of excitation-contraction coupling, which is fundamental for every heartbeat. However, the role and importance of RYR2 during human embryonic cardiac development are still poorly understood. Here, we generated two...

Sarcomeric cardiomyopathies are cardiovascular disorders that are caused by defects in genes encoding sarcomeric proteins. Depending on the location of the mutation within the gene, the disease phenotype manifests in different types of cardiac disorders, including hypertrophic and dilated cardiomyopathy, although mutations within the same gene can...

Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) provide a valuable source of human cardiomyocytes for biomedical studies. To induce iPSC-CM maturation by combining different stimuli, we designed a micro-physiological system (MPS) which mimics heart filling cycles through hemodynamic stimulation. To investigate the effect...

The increase in activity of the two-pore potassium-leak channel Kcnk5b maintains allometric juvenile growth of adult zebrafish appendages. However, it remains unknown how this channel maintains allometric growth and how its bioelectric activity is regulated to scale these anatomical structures. We show the activation of Kcnk5b is sufficient to acti...

Patient-specific induced pluripotent stem cells (ps-iPSCs) and their differentiated cell types are a powerful model system to gain insight into mechanisms driving early developmental and disease-associated regulatory networks. In this study, we use ps-iPSCs to gain insights into Tetralogy of Fallot (TOF), which represents the most common cyanotic h...

The adipocyte-derived adipokine leptin exerts pleiotropic effects, which are essential for the regulation of energy balance and cell metabolism, for controlling inflammatory and immune responses, and for the maintenance of homeostasis of the cardiovascular system. Leptin resistance in obese or type 2 diabetes mellitus (T2DM) patients is defined as...

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyoc...

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts....

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts....

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts....

1. Question: Cardiovascular diseases (CVDs) are a major cause of death and represent a global health challenge. Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) provide a valuable source of human cardiomyocytes for biomedical studies. The fetal-like phenotype of iPSC-CMs limits their application for pharmacological testing and...

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygo...

Sarcomeric cardiomyopathies are cardiovascular disorders that are caused by defects in genes encoding sarcomeric proteins. Depending on the location of the mutation within the gene, the disease phenotype manifests in different types of cardiac disorders, including hypertrophic and dilated cardiomyopathy, although mutations within the same gene can...

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and an...

Purpose: Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventri...

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have evolved into widely used and reliable cell sources for modeling cardiovascular channelopathies and for drug safety pharmacology. However, the electrophysiological and pharmacological applications of hiPSC-CMs are hampered by manual patch-clamp technique, which is labor-inte...

The lack of a fully developed human cardiac model in vitro hampers the progress of many biomedical research fields including pharmacology, developmental biology, and disease modeling. Currently, available methods may only differentiate human induced pluripotent stem cells (iPSCs) into immature cardiomyocytes. To achieve cardiomyocyte maturation, ap...

Chitin, as a fundamental polysaccharide in invertebrate skeletons, continues to be actively investigated, especially with respect to new sources and the development of effective methods for its extraction. Recent attention has been focused on marine crustaceans and sponges; however, the potential of spiders (order Araneae) as an alternative source...

Marine sponges remain representative of a unique source of renewable biological materials. The demosponges of the family Ianthellidae possess chitin-based skeletons with high biomimetic potential. These three-dimensional (3D) constructs can potentially be used in tissue engineering and regenerative medicine. In this study, we focus our attention, f...

Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are ty...

Recently, we could demonstrate positive effects of microfluidic cultivation conditions on maturation of cardiomyocytes derived from human induced pluripotent stem cells (iPS-CMs) in a 2D model. However, 3D cell culture models are much closer to physiological conditions. Combined with microfluidics, 3D systems should resemble the in-vivo conditions...

Diverse fields of modern technology and biomedicine can benefit from the application of ready-to-use chitin-based scaffolds. In this work we show for the first time the applicability of tubular and porous chitin from Caribena versicolor spiders as a scaffold for the development of an effective CuO/Cu(OH)2 catalyst for the reduction of 4-nitrophenol...

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibito...

Mutations in GNB5, encoding the G-protein β5 subunit (Gβ5), have recently been linked to a multisystem disorder that includes severe bradycardia. Here, we investigated the mechanism underlying bradycardia caused by the recessive p.S81L Gβ5 variant. Using CRISPR/Cas9-based targeting, we generated an isogenic series of human induced pluripotent stem...

Rationale: Secreted and membrane-bound proteins, which account for 1/3 of all proteins, play critical roles in heart health and disease. The endoplasmic reticulum (ER) is the site for synthesis, folding and quality control of these proteins. Loss of ER homeostasis and function underlies the pathogenesis of many forms of heart disease. Objective:...

Heart failure is the most common cause of morbidity and hospitalization in the western civilization. Protein phosphatases play a key role in the basal cardiac contractility and in the responses to β-adrenergic stimulation with type-1 phosphatase (PP-1) being major contributor. We propose here that formation of transient disulfide bridges in PP-1α m...

Fibrosis and inflammation promote atrial fibrillation (AF) and worsen its clinical outcome. The underlying molecular mechanisms, that are relevant for effective antifibrotic drug development, are still under debate. This study deciphers a novel mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-inflammatory cytokine osteopontin (OP...

Table S1. Expression Levels of Genes under Normoxic and Hypoxic Conditions in Wild-Type MEF Cells, Related to Figure 2

Table S2. Expression Levels of Genes under Normoxic and Hypoxic Conditions in TAZKO MEF Cells, Related to Figure 2

Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslati...

Increased sarcoplasmic reticulum (SR) Ca ²⁺ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca ²⁺ leak and improved survival in pressure overload (PO) and...

Heart failure is the most common cause of morbidity and hospitalization in the western civilization. Protein phosphatases (PP) play a key role in the basal cardiac contractility and in the responses to beta-adrenergic stimulation with type-1 phosphatase (PP-1) being major contributor. We propose here that formation of transient disulfide bridges in...

Generation of homogeneous populations of subtype-specific cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSCs) and their comprehensive phenotyping is crucial for a better understanding of the subtype-related disease mechanisms and as tools for the development of chamber-specific drugs. The goals of this study were to apply...

Hereby a microfluidic system for cell cultivation is presented in which human pluripotent stem cell-derived cardiomyocytes were cultivated under perfusion. Besides micro-perfusion this system is also capable to produce well-defined oxygen contents, apply defined forces and has excellent imaging characteristics. Cardiomyocytes attach to the surface,...

Background: Mutations in the PRKAG2 gene encoding the γ-subunit of adenosine monophosphate-kinase (AMPK) cause hypertrophic cardiomyopathy (HCM) and familial-Wolff-Parkinson-White syndrome (WPW). Patients carrying the R302Q mutation in PRKAG2 present sinus bradycardia, escape rhythms, ventricular pre-excitation, supraventricular tachycardia and at...

The ability to generate patient-specific induced pluripotent stem cells (iPSCs) provides a unique opportunity for modeling heart disease in vitro. In this study, we generated iPSCs from a patient with dilated cardiomyopathy (DCM) caused by a missense mutation S635A in RNA-binding motif protein 20 (RBM20) and investigated the functionality and cell...

Background: Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. Objectives: The aims of the study were to establish...

Natural killer (NK) cells play an important role as cytotoxic effector cells, which scan the organism for infected or tumorigenic cells. Conflicting data have been published whether NK cells can also kill allogeneic or even autologous pluripotent stem cells (PSCs) and which receptors are involved. A clarification of this question is relevant since...

Table S1. List of the Applied Primers Used for PCR Per Gene Table S2. Average Cell Capacitance and Series Resistance in All Experimental Groups. Values are Depicted as Mean±SEM Figure S1. Scheme of experimental approach depicting the different time points during differentiation at which the different steps, ie, addition of lactate, enzymatic diss...

BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate features of ion channel mutations causing inherited rhythm disease. However, the lack of maturity of these cells is considered a significant limitation of the model. Prolonged culture of hiPSC-CMs promotes maturation of these cells. We studied the e...