Human perinatal stem cell derived extracellular matrix enables rapid maturation of hiPSC-CM structural and functional phenotypes

Block, Travis J.; Creech, Jeffery; Rocha, A.M.; Marinkovic, Milos; Ponce-Balbuena, Daniela; Jiménez-Vázquez, Eric N.; Griffey, Sy; Herron, Todd J.

doi:10.1038/s41598-020-76052-y

Cited by 30 publications

(35 citation statements)

References 39 publications

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“…Indeed, the features of most 3D-ECTs made from cardiomyocytes derived from hiPSCs remain those of fetal or neonatal tissues [ 18 ]. Better maturation of the tissues can be achieved, first through maturation of the hiPSC-CMs before tissue formation [ 163 , 164 ] with long-term culture [ 165 ], biochemical cues [ 166 , 167 , 168 ], or biomimetic substrates [ 169 ]. Second, as explained earlier, adding electrical and/or mechanical stimulation of the tissues can further enhance their maturity [ 45 , 116 ].…”

Section: Limitations and Perspectives Of Cardiac Organoidsmentioning

confidence: 99%

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

et al. 2021

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Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the recent developments in cardiac tissue engineering have been made possible by important advances regarding the efficient generation of cardiac cells from pluripotent stem cells and the use of novel biomaterials and microfabrication methods. Different combinations of cells, biomaterials, scaffolds, and geometries are however possible, which results in different types of structures with gradual complexities and abilities to mimic the native cardiac tissue. Here, we intend to cover key aspects of tissue engineering applied to cardiology and the consequent development of cardiac organoids. This review presents various facets of the construction of human cardiac 3D constructs, from the choice of the components to their patterning, the final geometry of generated tissues, and the subsequent readouts and applications to model and treat cardiac diseases.

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Section: Limitations and Perspectives Of Cardiac Organoidsmentioning

confidence: 99%

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

et al. 2021

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“…We cultured and differentiated human iPS and ES cells into cardiomyocytes using the GiWi protocol, as described (42). Briefly, we seeded stem cells on Matrigel-coated plasticware with iPS-brew medium.…”

Section: Methodsmentioning

confidence: 99%

KCNH2encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

Jain

Stack

Ghodrati

et al. 2022

Preprint

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KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a novel hERG1 polypeptide (hERG1NP) that is targeted to the nuclei of immature cardiac cells, including hiPSC-CMs and neonatal rat cardiomyocytes. The nuclear hERG1NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished IKr and the hERG1NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking [alpha]; or [beta]1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the putative hERG1NP peptide in the nuclei of HEK cells significantly reduced hERG1a current density, compared to cells expressing the NLS-deficient hERG1NP or GFP. These data identify a developmentally regulated polypeptide encoded by KCNH2, hERG1NP, whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.

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“…This property leads to different expression profiles in ion channels and sarcomeric proteins, such as less organized sarcomeric structures and calcium‐handling machinery. 122 However, multiple efforts to overcome this limitation have been used recently, 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 including biochemical stimulation, electrical stimulation, mechanical stimulation, surface topography, substrate stiffness modification, 3D culture, long‐term culture of hiPSC‐CMs, and extracellular matrix culture (Table 4 ). All of these methods have been reported to improve hiPSC‐CM maturation.…”

Section: Experimental Models Of Brsmentioning

confidence: 99%

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

Lang

Akın

et al. 2022

JAHA

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Brugada syndrome (BrS) is an inherited and rare cardiac arrhythmogenic disease associated with an increased risk of ventricular fibrillation and sudden cardiac death. Different genes have been linked to BrS. The majority of mutations are located in the SCN5A gene, and the typical abnormal ECG is an elevation of the ST segment in the right precordial leads V1 to V3. The pathophysiological mechanisms of BrS were studied in different models, including animal models, heterologous expression systems, and human‐induced pluripotent stem cell–derived cardiomyocyte models. Currently, only a few BrS studies have used human‐induced pluripotent stem cell–derived cardiomyocytes, most of which have focused on genotype–phenotype correlations and drug screening. The combination of new technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR associated protein 9)‐mediated genome editing and 3‐dimensional engineered heart tissues, has provided novel insights into the pathophysiological mechanisms of the disease and could offer opportunities to improve the diagnosis and treatment of patients with BrS. This review aimed to compare different models of BrS for a better understanding of the roles of human‐induced pluripotent stem cell–derived cardiomyocytes in current BrS research and personalized medicine at a later stage.

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Human perinatal stem cell derived extracellular matrix enables rapid maturation of hiPSC-CM structural and functional phenotypes

Cited by 30 publications

References 39 publications

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

KCNH2encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

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