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

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

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival. Using human iPSC-derived cardiomyocytes to enhance cardiac drug discovery, Fiedler et al. performed MAP4K4 target validation by gene silencing in this human model. MAP4K4 inhibitors augment human cardiomyocyte viability and function in 2D culture and 3D engineered heart tissue. An exemplar successfully reduces infarct size in proof-of-principle studies in mice.

Original languageEnglish
Pages (from-to)579-591.e12
JournalCell stem cell
Volume24
Issue number4
DOIs
Publication statusPublished - 2019 Apr 4
Externally publishedYes

Keywords

  • apoptosis
  • cardiac muscle
  • drug discovery
  • heart
  • signal transduction

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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