Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity

Richards, Dylan; Li, Yang; Kerr, Charles M.; Yao, Jenny; Beeson, Gyda; Coyle, Robert C.; Chen, Xun; Jia, Jia; Damon, Brooke J.; Wilson, Robert; Hazard, E. Starr; Hardiman, Gary; Menick, Donald R.; Beeson, Craig C.; Yao, Hai; Ye, Tong; Mei, Ying

doi:10.1038/s41551-020-0539-4

Cited by 296 publications

(331 citation statements)

References 100 publications

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“…This has guided the development of engineered human cardiac tissue models that provide controlled environments to study cardiac development and disease along with drug toxicities in vitro 41,42 . Many technologies are being developed, including self-assembled spheroids/organoids 6,[43][44][45] , organ-on-a-chip 46,47 , and microtissue platforms 41,42,48 . In addition, to better mimic cardiac disease, pathological features are being introduced using hypoxia-induced apoptosis 6 , mechanical stress 49 , or varied cardiac cell ratios 50 .…”

Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

“…Many technologies are being developed, including self-assembled spheroids/organoids 6,[43][44][45] , organ-on-a-chip 46,47 , and microtissue platforms 41,42,48 . In addition, to better mimic cardiac disease, pathological features are being introduced using hypoxia-induced apoptosis 6 , mechanical stress 49 , or varied cardiac cell ratios 50 . Recent examples have also demonstrated how the introduction of electrical barriers such as holes in healthy cardiac tissue, or fibroblast dense regions can disrupt action potential propagation 45,51 .…”

Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

“…Engineered cardiac tissues are being widely used as models to study drug toxicities and efficacy in vitro 6,[42][43][44]59 . Here, we developed a fibrosis model that enabled the study of therapeutics for cardiac repair, including with functional outcomes to assess changes in contraction and electrophysiological properties.…”

Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

“…Cells possess the remarkable capacity to self-organize into multicellular spheroids in vitro, including from stem cells and into specialized organoid structures 1 . These spheroids are being used to emulate organs such as the intestine 2 , liver 3 , kidney 4 , brain 5 , and heart 6 to study human development and disease in vitro. In these formats they are promising as drug screening platforms due to their superior predictability and physiological structure and function when compared to traditional monolayer cultures [7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…High cell-densities are necessary to accurately recapitulate many pathological disease states such as cancer or fibrosis where perturbed cell-cell and cell-ECM interactions are central to disease progression. For example, spheroid cultures have enabled the engineering of heart, liver, and lung fibrosis models 6,[15][16][17][18] , and the presence of oxygen gradients with high cell densities mimics the cancer microenvironment [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

Daly

Burdick

2020

Preprint

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Cellular models are needed to study human development and disease in vitro, including the screening of drugs for toxicity and efficacy. However, current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a new bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprinted in vitro model is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and for the screening of drugs, particularly where high cell densities and heterogeneity are important.

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Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

Section: Bioprinting High-cell Density Tissue Models Through Direcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

Daly

Burdick

2020

Preprint

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Chemotherapeutics and CAR‐T Cell‐Based Immunotherapeutics Screening on a 3D Bioprinted Vascularized Breast Tumor Model

Dey

Kim

Dogan

et al. 2022

Adv Funct Materials

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Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically-relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic-flow based 3D bioprinted multi-scale vascularized breast tumor model, responding to chemo and immunotherapeutics is developed. Heterotypic tumors are precisely bioprinted at pre-defined distances from a perfused vasculature, exhibit tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of doxorubicin for 72 h portray a dose-dependent drug response behavior. More importantly, a cell based immune therapy approach is explored by perfusing HER2-targeting chimeric antigen receptor (CAR) modified CD8 + T cells for 24 or 72 h. Extensive CAR-T cell recruitment to the endothelium, substantial T cell activation and infiltration to the tumor site, resulted in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically-relevant tumor model for future translation of anti-cancer therapies to personalized medicine.

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Cobweb‐Inspired Microenvironment‐Targeting Nanosystem with Sequential Multiple‐Stage Stimulus‐Response Capacity for Ischaemic Tissue Repair

Ding

Xing

Liu

et al. 2023

Adv Funct Materials

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Myocardial ischaemia is pathologically complicated; various changes in intracellular and extracellular microenvironments make it essential to develop a smart drug system with multiple stimulus responses to adapt to the complex process. Inspired by the cobweb, this study designs a microreticular nanosystem that adheres to tissue and is sequentially responsive to multiple stimuli in the ischaemic microenvironment. The nanosystem is fabricated from hyaluronic acid (HA), ROS‐responsive B‐PDEA, and hypoxia‐sensitive VEGF‐expressing plasmids (EPODNA) through electrostatic interactions. After intramyocardial injection, the tissue‐adhesive property of the nanosystem will significantly decrease its acute loss from the injection site. Extracellularly, the microreticular nanosystem first responds to activated hyaluronidase (hyal), releasing HA for microenvironment regulation and B‐PDEA/DNA nanoparticles (NP) with high transfection efficiency for cardiac cells. Intracellularly, ROS sequentially induced B‐PDEA/DNA NP dissociation, consuming some ROS to attenuate oxidative stress and releasing DNA to promote its expression. Meanwhile, local hypoxia significantly activates VEGF expression in plasmids for myocardial revascularization and repair. The function of the microreticular nanosystem is systematically evaluated in vitro. In a rat model of myocardial infarction, treatment with the microreticular nanosystem significantly promotes functional and structural improvements. Collectively, the study provides a promising smart nanosystem to promote tissue repair after complex damage.

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Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity

Cited by 296 publications

References 100 publications

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

Chemotherapeutics and CAR‐T Cell‐Based Immunotherapeutics Screening on a 3D Bioprinted Vascularized Breast Tumor Model

Cobweb‐Inspired Microenvironment‐Targeting Nanosystem with Sequential Multiple‐Stage Stimulus‐Response Capacity for Ischaemic Tissue Repair

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