Novel Molecular Vehicle-Based Approach for Cardiac Cell Transplantation Leads to Rapid Electromechanical Graft–Host Coupling

Abstract

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy.

Biomimetic Cardiac Tissue Models for In Vitro Arrhythmia Studies

“…Moreover, a fragment of a single biocompatible polymer fiber of subcellular size may be used as a minimized "one-dimensional" polymer substrate itself. It was shown that fragments of PLLA or silk fibroin nanofibers with fibronectin coating may be used as effective scaffolds for solitary cardiomyocytes during cell transfer in vitro [158] and in vivo [159], supporting the organization of myofibrils and cytoskeleton of cells in suspension and restoring the cell excitability before adhesion to the recipient cell monolayer layer or tissue, respectively. Thus, such kernel substrates may be effectively used for in vitro modeling of cell transplantation processes in arrhythmia studies.…”

“…Cell transfer experiments in vivo show that the use of polymer kernel substrates leads to rapid electromechanical graft-host coupling: the synchronization of transplanted cells with isolated rat heart contractions (and consequently with each other) takes only 30 min after the first contact, while in the absence of any substrate, such a process may be chaotic, accompanied by engraftment arrhythmia, and would require several hours or even days [159].…”