MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Fiedler, Lorna R.; Chapman, Kathryn; Xie, Min; Maifoshie, Evie; Jenkins, Micaela; Golforoush, Pelin; Bellahcene, Mohamed; Noseda, Michela; Faust, Dörte; Jarvis, Ashley; Newton, Gary; Paiva, Marta; Harada, Mutsuo; Stuckey, Daniel J.; Song, Weihua; Habib, Josef; Narasimhan, P.; Aqil, Rehan; Sanmugalingam, Devika; Yan, Robert; Pavanello, Lorenzo; Sano, Motoaki; Wang, Sam C.; Sampson, Robert D.; Kanayaganam, Sunthar; Taffet, George E.; Michael, Lloyd H.; Entman, Mark L.; Tan, Tse‐Hua; Harding, Siân E.; Low, Caroline M. R.; Tralau-Stewart, Catherine; Perrior, Trevor; Schneider, Michael

doi:10.1016/j.stem.2020.01.015

Cited by 26 publications

(63 citation statements)

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“…Myocardial disease is a leading cause of morbidity and mortality in the world [33]. Due to the limited regenerative ability of the human heart following myocardial injury, stem cell-based therapies have served as a promising approach for improvement of cardiac repair and function [34,35]. A spectrum of stem cells has been searched for treating myocardial disease, including skeletal myoblasts, bone marrowderived cells, induced pluripotent stem cells, endothelial progenitor cells, and cardiac progenitor cells [2].…”

Section: Discussionmentioning

confidence: 99%

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

2020

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Aims: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIFpretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosome MIF), and delivered to cardiomyocytes subjected to H 2 O 2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. Exosome MIF protected cardiomyocytes from H 2 O 2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosome MIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosome MIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosome MIF inhibited H 2 O 2-induced apoptosis through modulating oxidative stress. Conclusions: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosome MIF in protecting cardiomyocytes from apoptosis.

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Section: Discussionmentioning

confidence: 99%

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

2020

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“…Cardiomyocyte viability and function (auxotonic force) were even preserved in human 3D engineered heart tissue 65 , a model with further maturity of structure and physiological properties 71 . Importantly, the pathway and compounds developed in hPSC-CMs were substantiated further by proof-of-concept studies in mice, with the MAP4K4 inhibitor reducing infarct size by more than 55% in blinded studies, even given an hour after injury 65 . These MAP4K4 studies demonstrate the pivotal role played by hPSC-CMs in validating a suspected target by gene silencing, then building a small-molecule program upon efficacy proven in this human platform.…”

Section: Heightening Fidelitymentioning

confidence: 95%

“…As a consequence, some pharmacological and pathobiological responses can be deficient or anomalous. In some reports, hPSC-CMs do not mirror the TdP risk of drugs with late sodium current effects, like ranolazine 32 , and hiPSC-CMs were less sensitive to hypoxia/reoxygenation than to other death signals 65,96,97 . Such disparities must be taken into account, whether inherent shortcomings or idiosyncratic.…”

Section: Challenges and Prospectsmentioning

confidence: 98%

“…While specific shortcomings in trial design or implementation are sometimes culpable, what these failed trials have in common uniformly is that none was based on proof of efficacy in human preclinical studies, before proceeding into the clinic. The use of hPSC-CMs toward drug discovery for cardioprotection was championed in our recent study creating novel inhibitors of the stress-activated kinase MAP4K4 (mitogen-activated protein kinase kinase kinase kinase-4) 65 , an upstream member of the MAPK superfamily with connections to Jun N-terminal kinase 66,67 and NFkB 68 , as well as to several non-canonical effectors as substrates 69,70 . The scientific case for MAP4K4 as a druggable target in heart muscle cell death began with human tissue characterization, finding that myocardial MAP4K4 was activated in end-stage heart failure regardless of cause (dilated, hypertrophic, ischemic, and anthracycline cardiomyopathy).…”

Section: Heightening Fidelitymentioning

confidence: 99%

“…Yet, even collectively, these methods-typical of the toolkit for academic target validation-leave altogether unanswered the question of whether MAP4K4 is a mechanistically sound therapeutic target in human heart muscle cell death. Consequently, using hPSC-CMs as a human platform for target validation and proof-of-concept studies, the requirement for MAP4K4 in human cardiac cell death was affirmed by gene silencing, giving uniquely direct impetus to a small-molecule discovery program 65 . Throughout, several high-throughput platforms were utilized, including automated microscopy (DRAQ7 uptake, TUNEL staining for apoptosis), ATP generation, and cardiac troponin release.…”

Section: Heightening Fidelitymentioning

confidence: 99%

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Intensive care for human hearts in pluripotent stem cell models

Golforoush

Schneider

2020

npj Regen Med

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Successful drug discovery is ultimately contingent on the availability of workable, relevant, predictive model systems. Conversely, for cardiac muscle, the lack of human preclinical models to inform target validation and compound development has likely contributed to the perennial problem of clinical trial failures, despite encouraging non-human results. By contrast, human cardiomyocytes produced from pluripotent stem cell models have recently been applied to safety pharmacology, phenotypic screening, target validation and high-throughput assays, facilitating cardiac drug discovery. Here, we review the impact of human pluripotent stem cell models in cardiac drug discovery, discussing the range of applications, readouts, and disease models employed, along with the challenges and prospects to advance this fruitful mode of research further.

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Biomimetic Design of Artificial Hybrid Nanocells for Boosted Vascular Regeneration in Ischemic Tissues

Zhang

et al. 2022

Advanced Materials

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Restoration of sufficient blood supply for the treatment of ischemia remains a significant scientific and clinical challenge. Here, a cell‐like nanoparticle delivery technology is introduced that is capable of recapitulating multiple cell functions for the spatiotemporal triggering of vascular regeneration. Specifically, a copper‐containing protein is successfully prepared using a recombinant protein scaffold based on a de novo design strategy, which facilitates the timely release of nitric oxide and improved accumulation of particles within ischemic tissues. Through closely mimicking physiological cues, the authors demonstrate the benefits of bioactive factors secreted from hypoxic stem cells on promoting angiogenesis. Following this cell‐mimicking manner, artificial hybrid nanosized cells (Hynocell) are constructed by integrating the hypoxic stem cell secretome into nanoparticles with surface coatings of cell membranes fused with copper‐containing protein. The Hynocell, hybridized with different cell‐derived components, provides synergistic effects on targeting ischemic tissues and promoting vascular regeneration in acute hindlimb ischemia and acute myocardial infarction models. This study offers new insights into the utilization of nanotechnology to potentiate the development of cell‐free therapeutics.

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MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Cited by 26 publications

References 0 publications

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

Intensive care for human hearts in pluripotent stem cell models

Biomimetic Design of Artificial Hybrid Nanocells for Boosted Vascular Regeneration in Ischemic Tissues

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