NC3Rs: National Centre for the Replacement Refinement & Reduction of Animals in Research
CRACK IT Challenge

Engineered 2D & 3D hiPSC-CM platforms to detect cardiovascular safety liabilities

A green graphic of a heart with a pulse signal behind it.

At a glance

In progress
Award date
July 2014
Contract amount
£999,915
Contractor(s)
Sponsor(s)

R

  • Replacement

Contents

Overview

Safety evaluation of drugs is a costly, protracted process that requires ~500,000 procedures on rodents, rabbits, dogs and primates in the UK annually. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could provide faster, more accurate safety testing, reducing costs and sparing thousands of animals. Because hiPSC-CM are in development, improvements are needed to integrate mature cells into platform(s) that simultaneously report on electrophysiology, calcium and contractility under (patho)physiological load.

The international consortium led by Prof Chris Denning from the University of Nottingham, comprises academic/SME partners with >50 person-years of expertise with stem cell-derived cardiomyocytes.

Phase 2 will further develop 2D, pseudo-3D and 3D platforms using cost-effective hiPSC-CMs produced in-house. Cell function will be improved via advanced media, flexible substrates and cell mixing. Researcher mobility will facilitate exchange of skills in cell engineering, hardware/software design, readouts and analysis, while in-kind contributions of compounds and data from the sponsor will enhance validation.

The team aims to offer a globally-competitive portfolio of screening platforms.

Full details about this CRACK IT Challenge can be found on the CRACK IT website.

Publications

  1. James V et al. (2021). Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo. Stem Cells and Development 30(24). doi: 10.1089/scd.2021.0202
  2. Mosqueira D et al. (2018). CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. European Heart Journal 39(43): 3879–3892. doi.org/10.1093/eurheartj/ehy249.
  3. Sala L et al. (2018). MUSCLEMOTION: A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo. Circulation Research 122: 5–16. doi.org/10.1161/CIRCRESAHA.117.312067
  4. Ulmer BM et al. (2018). Contractile Work Contributes to Maturation of Energy Metabolism in hiPSC-Derived Cardiomyocytes. Stem Cell Reports. doi: 10.1016/j.stemcr.2018.01.039
  5. van Meer BJ et al. (2017). Small molecule absorption by PDMS in the context of drug response bioassays. Biochemical and Biophysical Research Communications. doi.org/10.1016/j.bbrc.2016.11.062
  6. Duncan G et al. (2017). Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stem Cells and Development. doi: 10.1089/scd.2017.0172
  7. Giacomelli E et al. (2017). Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells. The Company of Biologists 144: 1008–17. doi:10.1242/dev.143438
  8. van Meer BJ, Tertoolen LGJ and Mummery CL (2016). Concise Review: Measuring Physiological Responses of Human Pluripotent Stem Cell Derived Cardiomyocytes to Drugs and Disease. Stem Cells 34(8): 2008–2015. doi: 10.1002/stem.2403
  9. Mannhardt I et al. (2016). Human Engineered Heart Tissue: Analysis of Contractile Force. Stem Cell Reports 7(1): 29–42. doi: 10.1016/j.stemcr.2016.04.011