In vitro aged, hiPSC-origin engineered heart tissue models with age-dependent functional deterioration to study myocardial infarction

Acun, Aylin; Nguyen, Trung Dung; Zorlutuna, Pınar

doi:10.1016/j.actbio.2019.05.064

Cited by 38 publications

(54 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the rest of this study, the two-step crosslinking method was used to create tissue constructs at a stiffness comparative to native human heart tissue (~10 kPa) [42]. For the swelling analysis, the volume of the hydrogels was measured after 24 hours incubation at 37 °C, allowing the gels to reach equilibrium swelling.…”

Section: Mechanical Characterization and Swellingmentioning

confidence: 99%

See 1 more Smart Citation

Tunable human myocardium derived decellularized extracellular matrix for 3D bioprinting and cardiac tissue engineering

Basara

Ozcebe

Ellis

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

The generation of 3D tissue constructs with multiple cell types and matching mechanical properties remains a challenge in cardiac tissue engineering. Recently, 3D bioprinting has become a powerful tool to achieve these goals. Decellularized extracellular matrix (dECM) is a common scaffold material due to providing a native biochemical environment. Unfortunately, low mechanical stability of dECM prevents usage for bioprinting applications alone. In this study, we developed bioinks composed of decellularized human heart ECM (dhECM) with either gelatin methacryloyl (GelMA) or GelMA- methacrylated hyaluronic acid (MeHA) hydrogels dual crosslinked with UV light and microbial Transglutaminase (mTGase). We characterized mechanical, rheological, swelling, printability and biocompatibility properties of the bioinks. Composite GelMA-MeHA-dhECM (GME) hydrogels demonstrated improved mechanical properties by an order of magnitude, compared to GelMA-dhECM (GE) hydrogels. All hydrogels were extrudable and compatible with human induced pluripotent stem cells derived cardiomyocytes (iCMs) and human cardiac fibroblasts (hCFs). Tissue-like beating of the printed constructs with striated sarcomeric alpha-actinin and Connexin 43 expression was observed. The order of magnitude difference between the elastic modulus of these hydrogel composites offers applications in in vitro modelling of the myocardial infarct boundary. Here, as a proof of concept, we created an infarct boundary region with control over mechanical properties along with cellular and macromolecular content through printing iCMs with GE bioink and hCFs with GME bioink.

show abstract

Section: Mechanical Characterization and Swellingmentioning

confidence: 99%

“…To analyze the contractility of iCMs, a block-matching algorithm was performed using MATLAB as described previously [42]. By using this method on the brightfield videos, the beating velocity and frequency of the iCMs were calculated and the heat maps were plotted.…”

Section: Beating and Phenotypical Characterizationmentioning

confidence: 99%

Tunable human myocardium derived decellularized extracellular matrix for 3D bioprinting and cardiac tissue engineering

Basara

Ozcebe

Ellis

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, modeling non-genetic pathologies mostly originating from insults to the adult heart in the late stages of cardiac development is within reach of 1,2 month-long cultures. While originally proposed as a maturation mechanism (Sartiani et al, 2007;Otsuji et al, 2010;Kamakura et al, 2013;Lundy et al, 2013), extended time in culture was recently extensively characterized over a 4-month period showing expression of aging markers in unprimed hPSC-CMs and increased sensitivity to I/R in disorganized 3D aggregates (Acun et al, 2019). To date, human engineered heart tissues (hEHTs) provide the closest match to an adult cardiomyocyte phenotype in vitro (Tiburcy et al, 2017;Ronaldson-Bouchard et al, 2018).…”

Section: Disease Modeling With 3d Constructsmentioning

confidence: 99%

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

2020

View full text Add to dashboard Cite

Non-genetic cardiac pathologies develop as an aftermath of extracellular stressconditions. Nevertheless, the response to pathological stimuli depends deeply on intracellular factors such as physiological state and complex genetic backgrounds. Without a thorough characterization of their in vitro phenotype, modeling of maladaptive hypertrophy, ischemia and reperfusion injury or diabetes in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has been more challenging than hereditary diseases with defined molecular causes. In past years, greater insights into hPSC-CM in vitro physiology and advancements in technological solutions and culture protocols have generated cell types displaying stress-responsive phenotypes reminiscent of in vivo pathological events, unlocking their application as a reductionist model of human cardiomyocytes, if not the adult human myocardium. Here, we provide an overview of the available literature of pathology models for cardiac non-genetic conditions employing healthy (or asymptomatic) hPSC-CMs. In terms of numbers of published articles, these models are significantly lagging behind monogenic diseases, which misrepresents the incidence of heart disease causes in the human population.

show abstract

“…were used for cardiomyocyte differentiation. The hiPSCs were maintained and differentiated using previously established protocols [37,41,99]. Briefly, hiPSCs were cultured on Geltrex (1%,…”

Section: Ipsc Cardiac Differentiation and Cell Culturementioning

confidence: 99%

Effect of Cellular and ECM Aging on Human iPSC-derived Cardiomyocyte Performance, Maturity and Senescence

Ozcebe

Bahçecioğlu

Yue

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Cardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here, we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell (iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking stress conditions in vitro. Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.

show abstract

In vitro aged, hiPSC-origin engineered heart tissue models with age-dependent functional deterioration to study myocardial infarction

Cited by 38 publications

References 109 publications

Tunable human myocardium derived decellularized extracellular matrix for 3D bioprinting and cardiac tissue engineering

Tunable human myocardium derived decellularized extracellular matrix for 3D bioprinting and cardiac tissue engineering

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

Effect of Cellular and ECM Aging on Human iPSC-derived Cardiomyocyte Performance, Maturity and Senescence

Contact Info

Product

Resources

About