Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Авг. 26, 2021

Abstract Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model accurately in vitro. Here we report a method generate developmentally relevant organoids self-assembly using pluripotent stem cells. Our procedure fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through three-step Wnt signaling modulation strategy chemical inhibitors growth factors. Heart comparable age-matched fetal cardiac tissues at transcriptomic, structural, cellular level. They develop sophisticated internal chambers well-organized multi-lineage cell types, recapitulate field formation atrioventricular specification, complex vasculature, exhibit robust functional activity. We also show that organoid platform can recreate metabolic associated congenital defects, as demonstrated an vitro pregestational diabetes-induced defects.

Язык: Английский

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Challenges and opportunities for the next generation of cardiovascular tissue engineering

Nature Methods, Год журнала: 2022, Номер 19(9), С. 1064 - 1071

Опубликована: Сен. 1, 2022

Язык: Английский

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Progress in multicellular human cardiac organoids for clinical applications

Cell stem cell, Год журнала: 2022, Номер 29(4), С. 503 - 514

Опубликована: Апрель 1, 2022

Язык: Английский

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Vascular cells improve functionality of human cardiac organoids

Cell Reports, Год журнала: 2023, Номер 42(5), С. 112322 - 112322

Опубликована: Апрель 26, 2023

Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular within human organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein optimize our protocol to generate populations addition epicardial, fibroblast, cardiomyocyte self-organize into in-vivo-like structures hCOs. We identify mechanisms communication endothelial cells, pericytes, fibroblasts, cardiomyocytes ultimately contribute organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression mature sarcomeric proteins contractility, (2) paracrine platelet-derived growth factor receptor β (PDGFRβ) signaling from upregulates matrix deposition augment hCO contractile force. Finally, demonstrate determine the magnitude diastolic dysfunction caused by inflammatory factors a role endothelin driving dysfunction. Together this study highlights importance models.

Язык: Английский

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Integrating organoids and organ-on-a-chip devices

Nature Reviews Bioengineering, Год журнала: 2024, Номер 2(7), С. 588 - 608

Опубликована: Июль 2, 2024

Язык: Английский

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Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Окт. 18, 2022

Abstract Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for studying personalized medicine and pre-clinical tests. Despite recent advances, that reproduce both complexity maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating human cardiac microtissues from hiPSCs—namely organotypic (hOCMTs)—that show some degree self-organization can be cultured long term. This achieved by differentiation hiPSC 2D monolayer culture towards lineage, followed further aggregation low-attachment dishes 3D. The generated hOCMTs contain multiple cell types compose heart beat without external stimuli more than 100 days. shown 3D display improved specification, survival metabolic as compared standard differentiation. also confirmed functionality their response cardioactive drugs long-term culture. Furthermore, we demonstrated they could used study chemotherapy-induced cardiotoxicity. Due showing tendency self-organization, cellular heterogeneity, our over extended time, confirm these constructs organoids (hCOs). help develop physiologically-relevant models, represent powerful platform future translational research biology.

Язык: Английский

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Cellular and Engineered Organoids for Cardiovascular Models

Circulation Research, Год журнала: 2022, Номер 130(12), С. 1780 - 1802

Опубликована: Июнь 9, 2022

An ensemble of in vitro cardiac tissue models has been developed over the past several decades to aid our understanding complex cardiovascular disorders using a reductionist approach. These approaches often rely on recapitulating single or multiple clinically relevant end points dish indicative pathophysiology. The possibility generate disease-relevant and patient-specific human induced pluripotent stem cells further leveraged utility as screening tools at large scale. To elucidate biological mechanisms models, it is critical integrate physiological cues form biochemical, biophysical, electromechanical stimuli achieve desired tissue-like maturity for robust phenotyping. Here, we review latest advances directed cell differentiation derive wide gamut types, allow customization model systems, study diseased states types. We also highlight recent progress development such organoids, microtissues, engineered heart tissues, microphysiological systems. expand discussion defining context use selection currently available models. Last, discuss limitations challenges with current state-of-the-art future directions.

Язык: Английский

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Biomanufacturing human tissues via organ building blocks

Cell stem cell, Год журнала: 2022, Номер 29(5), С. 667 - 677

Опубликована: Май 1, 2022

Язык: Английский

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3D organ-on-a-chip: The convergence of microphysiological systems and organoids

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Ноя. 21, 2022

Medicine today faces the combined challenge of an increasing number untreatable diseases and fewer drugs reaching clinic. While pharmaceutical companies have increased in early development entering phase I clinical trials, actually successfully pass III launch into market. In fact, only 1 out every 9 will launch.

Язык: Английский

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Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Март 31, 2022

The emergence of human induced pluripotent stem cells (hiPSCs) and efficient differentiation hiPSC-derived cardiomyocytes (hiPSC-CMs) from diseased donors have the potential to recapitulate molecular functional features heart. Although immaturity hiPSC-CMs, including structure, gene expression, conduct, ion channel density, Ca 2+ kinetics, is a major challenge, various attempts promote maturation been effective. Three-dimensional cardiac models using hiPSC-CMs achieved these morphological maturations, disease patient-specific furthered our understanding underlying mechanisms effective therapies for diseases. Aside diseases drug responses, also evaluate safety efficacy drugs in context before candidate enters market many phases clinical trials. In fact, novel testing paradigms suggested that can be used better predict proarrhythmic risk drugs. this review, we overview current strategies engineered heart tissue with focus on discuss perspectives future directions real application modeling, development, trials, cardiotoxicity tests.

Язык: Английский

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