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

Abstract

Highlights d Human iPSC-cardiomyocytes were used for MAP4K4 target validation and drug discovery d MAP4K4 shRNA protects hiPSC-cardiomyocytes from lethal oxidative stress d MAP4K4 inhibitors promote hiPSC-cardiomyocyte survival and function d MAP4K4 inhibition markedly reduces cardiac ischemiareperfusion injury in mice

Human pluripotent stem cell-derived cardiomyocytes as a target platform for paracrine protection by cardiac mesenchymal stromal cells

“…Although hPSC-CMs represent a scalable human platform for cardiac drug discovery reproducing many relevant features of cardiomyocytes' function, a few cautionary notes need to be highlighted. Cells used here include vCor4U that enrich for ventricular cardiomyocytes 23 , the relevant cells in a model of ischemic injury. Our RNA-seq data indicate that IMR-90 express cardiomyocytes' structural and functional genes in the absence of reprogramming genes, a proliferation signature or fibroblast markers.…”

“…Co-cultures were exposed to menadione, a naphthoquinone that induces endogenous reactive oxygen species (ROS) 32 , instrumental mediators of ischemia-reperfusion injury as in myocardial infarction ( Supplementary Fig. S1) 23,33,34 . As shown by the 56.5% inhibition of DRAQ7 uptake, co-culture with cMSCs protected the human cardiomyocytes from cell death after oxidative stress (p = 0.0007; Fig.…”

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

“…Priming hPSC-CMs through simple maturation steps generates cells responsive to I/R with mortality rates unseen in their unprimed counterparts, ultimately providing the biological model needed to test clinically effective small molecules (Hidalgo et al, 2018) or investigate the cardioprotective mechanism of cardiac progenitors (Sebastiao et al, 2019). The most intriguing example of in vitro I/R modeling to date fully embraces hPSC-CMs as platform for both drug screening and development (Fiedler et al, 2019). The researchers identify MAP4K4 as a druggable target, activity of which is altered across several clinically relevant heart failure models, and employ an I/R setup with primed hPSC-CMs to screen for suitable small-molecule inhibitors.…”

“…Currently, advanced modeling of the adult myocardium requires hEHTs. These multiparametric setups integrating stimulation and data acquisition systems, act as human preclinical models refining the predictive efficacy of less throughput-limited 2D hPSC-CM models (Fiedler et al, 2019). Nevertheless, while closely resembling adult tissue transcriptomic and functional features, hEHTs fall short of gaining the status of full-fledged organoids, not fully mimicking adult myocardial macroscopic ultrastructure (Tiburcy et al, 2017;Ronaldson-Bouchard et al, 2018), thus requiring additional bioengineering efforts to scale up the systems from tissue-to organ-models, as the recently proposed atrioventricular composite (Zhao et al, 2019).…”

“…Nearly two decades since their first description (Kehat et al, 2001), hPSC-CMs are beginning to fulfill their potential as a reductionist model of the human cardiac muscle. Thanks to constant improvements in differentiation protocols (Mummery et al, 2003;Laflamme et al, 2007;Yang et al, 2008;Kattman et al, 2011;Lian et al, 2012;Burridge et al, 2014) and increasing understanding of their in vitro cardiac phenotype, hPSC-CMs are now an integral part of proposed high-throughput drug screening (Kirby et al, 2018;Fiedler et al, 2019) and drug risk-assessment platforms (Yang and Papoian, 2018;Lu H.R. et al, 2019;Li et al, 2020).…”