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Targeting the Human Myocardial Remodeling Process Using Novel Magnetic Force-Based Human Heart Tissue

Periodic Reporting for period 1 - Magnetic HEART (Targeting the Human Myocardial Remodeling Process Using Novel Magnetic Force-Based Human Heart Tissue)

Reporting period: 2016-09-01 to 2018-08-31

Cardiovascular diseases are responsible for the greatest proportion of deaths in people under the age of 70 and cost the EU 110 billion Euros each year. A major cause of heart dysfunction following myocardial infarction is the extensive remodeling of the extracellular matrix (ECM), which leads to the formation of fibrotic scar and death of heart muscle cells - a collective process known as myocardial remodeling.

In this project, I developed a novel 3-dimensional (3D) human magnetic heart tissue based on unique magnetic nanoparticles (MNPs). Innovative MNPs were designed to target and specifically label human cardiomyocytes. By applying an external magnetic field, the magnetically labeled heart cells were accumulated to produce 3D human cardiac tissue in different sizes and shapes, which offer a practical alternative to native human heart tissue and for the monitoring of ECM remodeling process.

This new platform can possibly be translated to treat the remodeled area in the heart by restoring structure and function to the damaged heart tissue, and marks a major breakthrough in magnetic targeting therapy for lesions localized deeper in the body. The outcome of this research has the potential to impact health and society and become a vital component in therapeutic approaches to cardiovascular diseases.
The main findings and results obtained during the course of the project are:

• At the beginning of the project, MNPs were functionalized with a specific antibody to target human heart cells. In parallel, a well-defined protocol for differentiation of cardiomyocytes from human induced pluripotent stem cells (iPSCs) was established, obtaining >95% of pure human cardiomyocytes. In the next step, specific binding and uptake of the MNPs by the human heart cells was confirmed by transmitted electron microscopy (TEM) and Prussian blue assay. My findings indicated that the MNPs had no cytotoxicity effects on the cells and the cardiomyocytes were viable and functional for at least 21 days.

• I then aimed to construct the 3D magnetic human heart tissue. The first step was to validate that the magnetically labelled heart cells can form a viable constructing tissue. For that purpose, the cells were mixed in collagen suspension, and within 48-36 hours after gelation, I could already detect synchronous mechanical activity. I next demonstrated the ability to remotely control cardiomyocyte organization and distribution within a hydrogel by external magnetic fields. Different shapes and sizes of magnets were applied to generate intracellular magnetic forces that allowed the stimulation of the cells to the desired controlled geometries within the collagen hydrogel. The biochemical, morphological, and electrical properties of the generated 3D heart tissues were fully characterized by histological, gene expression, and electrophysiological methods.

• Finally, I focused on monitoring ECM remodeling in the generated 3D human cardiac tissue model by using the powerful tool of Raman spectroscopy. Raman spectra were acquired from a monolayer of human cardiomyocytes and different components in the cells (protein, lipid, DNA) were analyzed.

Final results overview: the unique approach developed in this project enables, for the first time, the construction of 3D human cardiac tissues with geometrically controlled microarchitecture without any supporting structures (such as micro-posts or thin films). Furthermore, it allows non-invasive and non-destructive analysis of cell viability and ECM turnover during cardiac remodelling.

A variety of techniques were employed to complete this project, ranging from the nanoscale where magnetic nanoparticles were functionalised with specific antibody and purified; through extensive cell work where cardiomyocytes were differentiated form human iPSCs – the interactions of the MNPs with the cells were confirmed by TEM and viability assays (such as MTT) – and finally in the macroscale by generating the novel 3D magnetic tissue followed by detailed characterizations by confocal microscopy / immunocytochemistry, optical mapping (calcium handling and multielectrode array) and molecular biology techniques such as quantitative polymerase chain reaction (qPCR).

Dissemination of the results: This work has been presented during 2018 at two international conferences (Gordon Research Conference, Les Diablerets, Switzerland; TERMIS World Congress, Kyoto, Japan) and at three national meetings (BCS Annual Conference, Manchester UK; Satellite meeting on Cardiac Physiology, London UK; and FILM microscopy day at Imperial College London). In addition, a high-level manuscript is currently under preparation to be submitted to high-quality journal.

Outreach activities: On March 2018, this work was selected to be presented in the prestigious and highly competitive STEM for BRITIAN poster competition for early-career researches, where I had the opportunity to present and talk about “Magnetic HEART” project in front of Members of both Houses of Parliament at Westminster, London. In addition, during the two-year funding period, extensive outreach activities were carried out to engage with young students and expose them to different aspects of science. For example, in July 2017 and July 2018 I gave several hands-on demons
It is predicted that myocardial regenerative therapy can be a viable treatment for patients with severe heart failure and ischemic heart diseases. In “Magnetic HEART” I developed a new and simple approach for fabricating a 3D engineered heart construct where the cells organisation can be controlled by external magnetic fields. This new type of engineered heart tissue, without the use of any external mechanical supports, represents a major innovation in the field of myocardial tissue engineering and tackles the global issue of cardiovascular diseases, a major cause of mortality and morbidity in the world. The knowledge gained from this project will be very beneficial for the further development research in myocardial regeneration, such as targeted cell-delivery and targeted drug-delivery approaches with global implications for personalized healthcare.