Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips

Huebsch, Nathaniel; Charrez, Bérénice; Neiman, Gabriel; Siemons, Brian; Boggess, Steven; Wall, Samuel; Charwat, Verena; Jæger, Karoline Horgmo; Cleres, David; Telle, Åshild; Lee-Montiel, Felipe T.; Jeffreys, Nicholas; Deveshwar, Nikhil; Edwards, Andrew G.; Serrano, Jonathan; Snuderl, Matija; Stahl, Andreas; Tveito, Aslak; Miller, Evan W.; Healy, Kevin E.

doi:10.1038/s41551-022-00884-4

Cited by 57 publications

(52 citation statements)

References 98 publications

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“…Electrical stimulation that acts as pacemaker cells plus the stretch and fluidic stimulations that mimic the stretch force and hemodynamic shear force produced by CM contraction and blood flow, respectively, all have been shown to enhance SC-CM maturation. The maturation of SC-CMs has also been reported by providing them with a FA-enriched, glucose-depleted environment that fit the metabolic characteristics of mature CMs ( Correia et al, 2017 ; Lin et al, 2017 ; Horikoshi et al, 2019 ; Yang et al, 2019 ; Feyen et al, 2020 ; Knight et al, 2021 ; Huebsch et al, 2022 ), or activating PPARs that facilitate fatty-acid oxidation ( Gentillon et al, 2019 ; Lopez et al, 2021 ; Wickramasinghe et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is thought that uniaxial stress alone is insufficient in representing the in vivo mechanical environment in which the heart develops and matures ( Shen et al, 2017 ). In light of this, several teams have aimed at developing platforms that can replicate the natural hemodynamic environment ( Shen et al, 2017 ; Kolanowski et al, 2020 ; Veldhuizen et al, 2020 ; Huebsch et al, 2022 ). To date, several reports of microfluidic systems that provide such hemodynamic fluidic stress have been proven to mature the structural and functional properties of hSC-CMs.…”

Section: Mechanical Cuesmentioning

confidence: 99%

“…These systems typically feature gravity- or pump-driven dynamic pulsatile flow with adjustable velocity, which creates not only shear stress but also dynamic pressure [respectively 0.71 dyn cm −2 and 15 mmHg, in accordance with ( Kolanowski et al, 2020 )]. Additionally, these systems can be designed to incorporate co-culture with niche cells ( Veldhuizen et al, 2020 ), control of oxygen levels ( Kolanowski et al, 2020 ), metabolic ( Huebsch et al, 2022 ) and geometric engineering ( Veldhuizen et al, 2020 ), thus providing multifaceted potentials to promote hSC-CM maturation. While current cell chambers in microfluidic systems are limited in size, the microfluidic systems have the potential of high-throughput culturing of CMs, unlike uniaxial stretching systems in which CMs are typically treated in the form of single cells or CM-based stripes to ensure optimal force direction ( Kolanowski et al, 2020 ).…”

Section: Mechanical Cuesmentioning

confidence: 99%

“…The glucose-rich microenvironment provided by media like RPMI-B27-insulin can also hinder the metabolic maturation of CMs by inhibiting FAO ( Nakano et al, 2017 ; Feyen et al, 2020 ). Based on these findings, various low-glucose, FA-supplemented maturation media have been developed to improve the structural, functional, pharmacological, and especially metabolic maturation of hESC- and hiPSC-CMs ( Correia et al, 2017 ; Lin et al, 2017 ; Horikoshi et al, 2019 ; Yang et al, 2019 ; Feyen et al, 2020 ; Knight et al, 2021 ; Huebsch et al, 2022 ).…”

Section: Metabolic Engineeringmentioning

confidence: 99%

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Engineering the maturation of stem cell-derived cardiomyocytes

Yang

Zhao

et al. 2023

Front. Bioeng. Biotechnol.

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The maturation of human stem cell-derived cardiomyocytes (hSC-CMs) has been a major challenge to further expand the scope of their application. Over the past years, several strategies have been proven to facilitate the structural and functional maturation of hSC-CMs, which include but are not limited to engineering the geometry or stiffness of substrates, providing favorable extracellular matrices, applying mechanical stretch, fluidic or electrical stimulation, co-culturing with niche cells, regulating biochemical cues such as hormones and transcription factors, engineering and redirecting metabolic patterns, developing 3D cardiac constructs such as cardiac organoid or engineered heart tissue, or culturing under in vivo implantation. In this review, we summarize these maturation strategies, especially the recent advancements, and discussed their advantages as well as the pressing problems that need to be addressed in future studies.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanical Cuesmentioning

confidence: 99%

Section: Mechanical Cuesmentioning

confidence: 99%

Section: Metabolic Engineeringmentioning

confidence: 99%

See 2 more Smart Citations

Engineering the maturation of stem cell-derived cardiomyocytes

Yang

Zhao

et al. 2023

Front. Bioeng. Biotechnol.

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“…For example, the EHT formed in the chip could be electrically stimulated by 3D electrodes integrated in the chip, and endothelialization could also be induced through separate channels ( 43 ). Moreover, EHT fabricated using human iPSC-derived CMs (80%) and human iPSC-derived stromal cells (20%) within microfluidic chip showed an increase in cellular alignment and ECM production, and further matured under medium condition enriched with fatty acids ( 44 ).…”

Section: Engineered Cardiac Tissue Modelsmentioning

confidence: 99%

Engineered human cardiac tissues for modeling heart diseases

Min¹,

Cho

2022

BMB Rep

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Heart disease is one of the major life-threatening diseases with high mortality and incidence worldwide. Several model systems, such as primary cells and animals, have been used to understand heart diseases and establish appropriate treatments. However, they have limitations in accuracy and reproducibility in recapitulating disease pathophysiology and evaluating drug responses. In recent years, three-dimensional (3D) cardiac tissue models produced using tissue engineering technology and human cells have outperformed conventional models. In particular, the integration of cell reprogramming techniques with bioengineering platforms ( e.g. , microfluidics, scaffolds, bioprinting, and biophysical stimuli) has facilitated the development of heart-on-a-chip, cardiac spheroid/organoid, and engineered heart tissue (EHT) to recapitulate the structural and functional features of the native human heart. These cardiac models have improved heart disease modeling and toxicological evaluation. In this review, we summarize the cell types for the fabrication of cardiac tissue models, introduce diverse 3D human cardiac tissue models, and discuss the strategies to enhance their complexity and maturity. Finally, recent studies in the modeling of various heart diseases are reviewed.

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Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites

Dickerson

2022

Advanced Biology

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A heart attack results in the permanent loss of heart muscle and can lead to heart disease, which kills more than 7 million people worldwide each year. To date, outside of heart transplantation, current clinical treatments cannot regenerate lost heart muscle or restore full function to the damaged heart. There is a critical need to create engineered heart tissues with structural complexity and functional capacity needed to replace damaged heart muscle. The inextricable link between structure and function suggests that hydrogel composites hold tremendous promise as a biomaterial‐guided strategy to advance heart muscle tissue engineering. Such composites provide biophysical cues and functionality as a provisional extracellular matrix that hydrogels cannot on their own. This review describes the latest advances in the characterization of these biomaterial systems and using them for heart muscle tissue engineering. The review integrates results across the field to provide new insights on critical features within hydrogel composites and perspectives on the next steps to harnessing these promising biomaterials to faithfully reproduce the complex structure and function of native heart muscle.

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Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips

Cited by 57 publications

References 98 publications

Engineering the maturation of stem cell-derived cardiomyocytes

Engineering the maturation of stem cell-derived cardiomyocytes

Engineered human cardiac tissues for modeling heart diseases

Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites

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