Generation of high-performance human cardiomyocytes and engineered heart tissues from extended pluripotent stem cells

Li, Li; Wan, Zhongjun; Wang, Ruxiang; Zhao, Yuliang; Ye, Yida; Yang, Pengcheng; Yan, Qi; Jiang, Wei; Chen, Lin; Zhang, Donghui

doi:10.1038/s41421-022-00446-7

Cited by 11 publications

(6 citation statements)

References 11 publications

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“…Furthermore, in Tyrode solution a subset of bCM EHTs was successfully captured at 4 Hz pacing (Fig. S6g-j; Movie S8), notably faster than the previously reported maximal rates achieved for EHTs [32][33][34] without physical conditioning 35,36 .…”

Section: Bcms Show High Force Development and Maturity In 3d Engineer...mentioning

confidence: 56%

“…Here we present a lower-cost bioreactor-based cardiac differentiation protocol (~$569 per bioreactor run yielding ~124 million hiPSC-CMs, compared to ~$1075 for ML differentiation with comparable yield, exclusive of manpower; Table S3) with defined benchmarks and controlled freeze/thaw procedures. We extensively characterized the resulting bCMs and demonstrated that they have robust structural and functional properties of cardiomyocytes, reduced batch-to-batch variation, and greater force production in EHTs than previously described 5,[16][17][18][32][33][34]36 . These levels of force were comparable to EHTs that underwent physical conditioning of increasing intensity 35 .…”

Section: Discussionmentioning

confidence: 91%

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Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor

Prondzynski,

Bortolin,

Berkson

et al. 2024

Preprint

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In the last decade human iPSC-derived cardiomyocytes (hiPSC-CMs) proved to be valuable for cardiac disease modeling and cardiac regeneration, yet challenges with scale, quality, inter-batch consistency, and cryopreservation remain, reducing experimental reproducibility and limiting clinical translation. Here, we report a robust cardiac differentiation protocol that uses Wnt modulation and a stirred suspension bioreactor to produce on average 124 million hiPSC-CMs with >90% purity using a variety of hiPSC lines (19 differentiations; 10 iPSC lines). After controlled freeze and thaw, bioreactor-derived CMs (bCMs) showed high viability (>90%), interbatch reproducibility in cellular morphology, function, drug response and ventricular identity, which was further supported by single cell transcriptomes. bCMs on microcontact printed substrates revealed a higher degree of sarcomere maturation and viability during long-term culture compared to monolayer-derived CMs (mCMs). Moreover, functional investigation of bCMs in 3D engineered heart tissues showed earlier and stronger force production during long-term culture, and robust pacing capture up to 4 Hz when compared to mCMs. bCMs derived from this differentiation protocol will expand the applications of hiPSC-CMs by providing a reproducible, scalable, and resource efficient method to generate cardiac cells with well-characterized structural and functional properties superior to standard mCMs.

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Section: Bcms Show High Force Development and Maturity In 3d Engineer...mentioning

confidence: 56%

Section: Discussionmentioning

confidence: 91%

Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor

Prondzynski,

Bortolin,

Berkson

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Human cardiomyocytes derived from hiPSCs (human Induced pluripotent stem cells) in our experiments were developed according to previous studies [ 42 ]. hiPSCs were cultured in mTeSR TM 1 for 3 days, and then administrated by Wnt signaling modulators.…”

Section: Methodsmentioning

confidence: 99%

TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53

Gong,

Zhai,

Shi

et al. 2024

Cell Death Differ

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Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC–MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.

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“…We have previously established the engineered human heart tissue ("cardiobundles" and "cardiopatterns") amenable to studies of myocardial function and drug response. [17][18][19] In the present study, we have clarified the specific regulatory mechanism and reparative effect of IL-37 on HF-related hiPSC-CM and human heart tissue using hypoxia and H 2 O 2 treatment. We have revealed IL-37 increases cell viability, calcium transient levels, contractile force, and Ca 2+ conduction capacity and also promotes the expression of SERCA2a, this effect was mediated by enhancing nuclear p-STAT3 level via binding to the promoter of SERCA2a.…”

Section: Introductionmentioning

confidence: 97%

IL‐37 Modulates Myocardial Calcium Handling via the p‐STAT3/SERCA2a Axis in HF‐Related Engineered Human Heart Tissue

Yin,

Liu,

Xue

et al. 2024

Adv Healthcare Materials

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Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine belonging to the IL‐1 family. This study investigates the regulatory mechanism and reparative effects of IL‐37 on HF‐related human induced pluripotent stem cells derived cardiomyocytes (hiPSC‐CMs) and engineered human heart tissue subjected to hypoxia and H2O2 treatment. The contractile force and Ca2+ conduction capacity of the tissue were assessed using a stretching platform and high‐resolution fluorescence imaging system. Our investigation reveals that IL‐37 treatment significantly enhances cell viability, calcium transient levels, contractile force and Ca2+ conduction capacity in HF‐related hiPSC‐CMs and engineered human heart tissue. Notably, IL‐37 facilitates the upregulation of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) through enhancing nuclear p‐STAT3 levels. This effect is mediated by the binding of p‐STAT3 to the SERCA2a promoter, providing a novel insight on the reparative potential of IL‐37 in HF. IL‐37 demonstrates its ability to enhance systolic function by modulating myocardial calcium handling via the p‐STAT3/SERCA2a axis in HF‐related engineered human heart tissue (as shown in schematic diagram).This article is protected by copyright. All rights reserved

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Generation of high-performance human cardiomyocytes and engineered heart tissues from extended pluripotent stem cells

Cited by 11 publications

References 11 publications

Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor

Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor

TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53

IL‐37 Modulates Myocardial Calcium Handling via the p‐STAT3/SERCA2a Axis in HF‐Related Engineered Human Heart Tissue

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