In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

Davis, Justin A.; Chouman, Ahmad; Creech, Jeffery; Rocha, A.M.; Ponce-Balbuena, Daniela; Jiménez-Vázquez, Eric N.; Nichols, Robert C.; Lozhkin, Andrey; Madamanchi, Nageswara R.; Campbell, Katherine; Herron, Todd J.

doi:10.1172/jci.insight.134368

Cited by 24 publications

(26 citation statements)

References 55 publications

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“…The SAN differentiation protocol involves a metabolic-based selection step, which has been suggested to produce a heart failure-like phenotype. 38 To confirm that SARS-CoV-2 infection and ferroptosis are independent of metabolic-based selection, we also infected the hESC-SAN–like pacemaker population without metabolic-based selection ( Figure S1G ). Consistent with the experiments using hESC-SAN–like pacemaker cells derived with metabolic selection protocol, SARS-N viral antigen was detected in SHOX2:GFP + MYH6:mCherry + SAN-like pacemaker cells derived without metabolic selection ( Figure S4H ).…”

Section: Resultsmentioning

confidence: 89%

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

Han

Zhu

Yang

et al. 2022

Circulation Research

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Background: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. Methods: We used both a hamster model and human ESC (hESC)–derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN–like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2–induced ferroptosis. Results: Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. Conclusions: Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 89%

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

Han

Zhu

Yang

et al. 2022

Circulation Research

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“…Clearly treatment duration, metabolic stress, and maturation of hiPSC-CMs contribute to the degree of toxic responses. Concerns raised by a recent report indicate that the metabolic selection method may mimic ischemic conditions, upon analysis being carried out within 4 days of metabolic selection (51). In contrast, we performed our phenotype characterization after culturing hiPSC-CMs in glucose-containing medium for 15-20 days, a timeframe during which these cells are presumed to have recovered from metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment

Stern¹,

Liang²,

Li³

et al. 2022

JCI Insight

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“…hiPSC-derived CMs have been used for the development of several in vitro disease models [31][32][33]. They have shown to be promising for studies of cardiac hypertrophy, with characteristics resembling the in vivo situation.…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy

Johansson

Ulfenborg

Andersson

et al. 2022

Life

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Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization using a multi-omics approach. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48, and 72 h, and their transcriptome and secreted proteome were analyzed. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling. An integrated transcriptome–secretome analysis enabled the identification of multimodal biomarkers that may prove highly relevant for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on both transcriptomic- and secreted-proteomic levels. The results also shed novel insights into the underlying mechanisms of cardiac hypertrophy, and novel putative early cardiac hypertrophy biomarkers have been identified that warrant further investigation to assess their potential clinical relevance.

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In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

Abstract: are consultants to CARTOX, Inc.; Todd J. Herron is co-founder of and has financial interest in CARTOX, Inc. CARTOX, Inc. is a Michigan company focused on the development of novel hiPSC-CM based assays for cardiotoxicity screening. T.J.H is also a consultant to StemBioSys, Inc.

Cited by 24 publications

References 55 publications

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment

Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy

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