Real-Time Force and Frequency Analysis of Engineered Human Heart Tissue Derived from Induced Pluripotent Stem Cells Using Magnetic Sensing

Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

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Real-time simulation of IK1 in cardiomyocytes derived from human induced pluripotent stem cells

2015 Computing in Cardiology Conference (CinC) ◽

10.1109/cic.2015.7408610 ◽

2015 ◽

Author(s):

Rosalie ME Meijer van Putten ◽

Isabella Mengarelli ◽

Kaomei Guan ◽

Jan G Zegers ◽

Antoni CG van Ginneken ◽

...

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Real Time ◽

Pluripotent Stem Cells ◽

Real Time Simulation ◽

Time Simulation ◽

Induced Pluripotent

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Uncovering Inherited Cardiomyopathy With Human Induced Pluripotent Stem Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.672039 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xue Jiang ◽

Yihuan Chen ◽

Xiaofeng Liu ◽

Lingqun Ye ◽

Miao Yu ◽

...

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Human Heart ◽

Heart Diseases ◽

Patient Specific ◽

Inherited Cardiomyopathy ◽

Inherited Cardiomyopathies ◽

Induced Pluripotent

In the past decades, researchers discovered the contribution of genetic defects to the pathogenesis of primary cardiomyopathy and tried to explain the pathogenesis of these diseases by establishing a variety of disease models. Although human heart tissues and primary cardiomyocytes have advantages in modeling human heart diseases, they are difficult to obtain and culture in vitro. Defects developed in genetically modified animal models are notably different from human diseases at the molecular level. The advent of human induced pluripotent stem cells (hiPSCs) provides an unprecedented opportunity to further investigate the pathogenic mechanisms of inherited cardiomyopathies in vitro using patient-specific hiPSC-derived cardiomyocytes. In this review, we will make a summary of recent advances in in vitro inherited cardiomyopathy modeling using hiPSCs.

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Abstract 15466: Bioactive Contents and Cardiovascular Regenerative Potential of Extracellular Vesicles Derived From Induced Pluripotent Stem Cells

Circulation ◽

10.1161/circ.132.suppl_3.15466 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Marta Adamiak ◽

Sylwia Bobis-Wozowicz ◽

Elzbieta Karnas ◽

Sylwia Kedracka-Krok ◽

Michal Sarna ◽

...

Keyword(s):

Stem Cells ◽

Flow Cytometry ◽

Endothelial Cells ◽

Induced Pluripotent Stem Cells ◽

Real Time ◽

Extracellular Vesicles ◽

Pluripotent Stem Cells ◽

Target Cells ◽

Rt Pcr ◽

Induced Pluripotent

Introduction: Extracellular vesicles (EVs) are tiny membrane-enclosed vesicles released by cells by membrane budding or exocytosis. The molecular profile of contents and regenerative potential of EVs derived from murine induced pluripotent stem cells (miPSCs) have not been investigated. Hypothesis: We hypothesized that miPSC-derived EVs carry bioactive substances, including mRNA and miRNA, which would influence the biology and fate of target cells. Methods: Murine iPSCs were generated using established protocols and EVs were isolated from culture supernatants by sequential centrifugation. Atomic force microscopy (AFM), flow cytometry, and real-time RT-PCR were used to characterize EV contents. Endothelial cells were exposed to miPSC-EVs in culture. Results: AFM and dynamic light scattering showed that miPSC-EVs are homogenous spherical vesicles smaller than 100 nm (Fig, A). High-sensitivity flow cytometry confirmed the presence of several iPSC- specific markers along with typical exosomal markers (CD9, CD63 and CD81) on miPSC-EVs. miPSC-EVs were enriched in mRNAs, miRNAs and proteins from donor iPSCs as shown by real-time RT-PCR and mass spectroscopy, respectively. Moreover, miPSC-EVs contained transcripts regulating pluripotency, self-renewal and differentiation, including Oct-4, Nanog, GATA-4 as well as miR290-295 cluster (Fig, B,C). Importantly, several miRNAs were found to be higher in EVs when compared with parental miPSCs (Fig, B,C). Endothelial cells treated with miPSC-EVs exhibited greater proliferative, metabolic and angiogenic activities, and were more resistant to apoptosis. Conclusions: Our data show, for the first time, that miPSC-derived EVs are natural nanocarriers capable of transferring bioactive contents to mature cells affecting target cell function as well as regenerative potential. We conclude that iPSC-EVs may represent safe therapeutic alternatives to whole cell-based therapy for cardiovascular repair.

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Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells

Science Translational Medicine ◽

10.1126/scitranslmed.aaf8781 ◽

2016 ◽

Vol 8 (363) ◽

pp. 363ra148-363ra148 ◽

Cited By ~ 106

Author(s):

F. Weinberger ◽

K. Breckwoldt ◽

S. Pecha ◽

A. Kelly ◽

B. Geertz ◽

...

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Guinea Pigs ◽

Heart Tissue ◽

Cardiac Repair ◽

Engineered Heart Tissue ◽

Induced Pluripotent

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Ontogenic development of cardiomyocytes derived from transgene-free human induced pluripotent stem cells and its homology with human heart

Life Sciences ◽

10.1016/j.lfs.2012.10.020 ◽

2013 ◽

Vol 92 (1) ◽

pp. 63-71 ◽

Cited By ~ 12

Author(s):

Glen Lester Sequiera ◽

Ashish Mehta ◽

Ting Huay Ooi ◽

Winston Shim

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Human Heart ◽

Ontogenic Development ◽

Induced Pluripotent

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Translational potential of human embryonic and induced pluripotent stem cells for myocardial repair: Insights from experimental models

Thrombosis and Haemostasis ◽

10.1160/th10-03-0189 ◽

2010 ◽

Vol 104 (07) ◽

pp. 30-38 ◽

Cited By ~ 46

Author(s):

Chi-Wing Kong ◽

Fadi Akar ◽

Ronald Li

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Human Heart ◽

Heart Diseases ◽

Embryonic Stem ◽

Developed Countries ◽

Heart Cells ◽

Myocardial Repair ◽

Induced Pluripotent

SummaryHeart diseases have been a major cause of death worldwide, including developed countries. Indeed, loss of non-regenerative, terminally differentiated cardiomyocytes (CMs) due to aging or diseases is irreversible. Current therapeutic regimes are palliative in nature, and in the case of end-stage heart failure, transplantation remains the last resort. However, this option is significantly hampered by a severe shortage of donor cells and organs. Human embryonic stem cells (hESCs) can self-renew while maintaining their pluripotency to differentiate into all cell types. More recently, direct reprogramming of adult somatic cells to become pluripotent hES-like cells (a.k.a. induced pluripotent stem cells or iPSCs) has been achieved. The availability of hESCs and iPSCs, and their successful differentiation into genuine human heart cells have enabled researchers to gain novel insights into the early development of the human heart as well as to pursue the revolutionary paradigm of heart regeneration. Here we review our current knowledge of hESC-/iPSC-derived CMs in the context of two fundamental operating principles of CMs (i.e. electrophysiology and Ca2+-handling), the resultant limitations and potential solutions in relation to their translation into clinical (bioartificial pacemaker, myocardial repair) and other applications (e.g. as models for human heart disease and cardiotoxicity screening).

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