Living myocardial slices: a novel multicellular model for cardiac translational research

Abstract

Heart function relies on the interplay of several specialized cell types and a precisely regulated network of chemical and mechanical stimuli. Over the last few decades, this complexity has often been undervalued and progress in translational cardiovascular research has been significantly hindered by the lack of appropriate research models. The data collected are often oversimplified and these make the translation of results from the laboratory to clinical trials challenging and occasionally misleading. Living myocardial slices are ultrathin (100-400μm) sections of living cardiac tissue that maintain the native multicellularity, architecture, and structure of the heart and can provide information at a cellular/subcellular level. They overcome most of the limitations that affect other in vitro models and they can be prepared from human specimens, proving a clinically relevant multicellular human model for translational cardiovascular research. The publication of a reproducible protocol, and the rapid progress in methodological and technological discoveries which prevent significant structural and functional changes associated with chronic in vitro culture, has overcome the last barrier for the in vitro use of this human multicellular preparations. This technology can bridge the gap between in vitro and in vivo human studies and has the potential to revolutionize translational research approaches.

Keywords: Living myocardial slices; Translational research.

Figure 1

Flowchart of living myocardial slice preparation, chronic culture, and ex vivo experimental measurements. Living myocardial slices are prepared with both animal and human cardiac specimens. They can be used acutely or following in vitro chronic culture to investigate several functional, structural, or biochemical parameters. Images in this figure have been previously published.^,

Figure 2

Contractility recordings and representative confocal images of living myocardial slice. (A) Schematic illustration of contractility parameters (TP = Time to Peak, T50% = Time to 50% relaxation, T90% = Time to 90% relaxation, Decay Rate). (B) Representative traces of the contractile capacity of two myocardial slices displaying a faster (red) and slower (blue) contraction and relaxation kinetics. (C–F) Wheat germ agglutinin (WGA) staining allows the visualization of cell membrane and it is used to study cardiomyocytes dimensions and T-tubule organization. Immunohistochemical staining for Collagen, Connexin43, and Caveolin 3 were used to visualize collagen organization, gap junction distribution, and cardiomyocytes morphology.^,