Pseudohypoxia-mediated cardiac regeneration

Ischemic heart disease is the main cause of death in Europe and the world, and its main manifestation is myocardial infarction (MI). The MI leads to loss of heart tissue, tissue scarring associated with fibrosis, dysfunction and heart failure. The pathophysiological basis of heart failure in humans lies in the heart's inability to regenerate.

Adult cardiomyocytes (CMs) perform mitosis after MI, but their proliferation rate is extremely low for restoring normal cardiac function.

During development, low levels of intrauterine oxygen promote the proliferation of CMs, which decreases postpartum due to the metabolic adaptation that implies exposure to atmospheric oxygen.

Induced hypoxia in adult mammals promotes proliferation of CMs, and is required for cardiac regeneration (CR) of teleost such as zebrafish. However, the mechanisms that mediate these effects are unclear.

Systemic exposure to hypoxia has been proposed as a strategy to promote CR; however, its adverse effects on other vital organs limit its clinical use. Here, we have proposed the generation of a temporary and localized hypoxia in the infarcted area of the heart.

To achieve this, we will synthesize fibrin scaffolds bearing FG-4592 - an agent that mimics the effects of hypoxia (pseudohypoxia) - using bioprinting 3D.

Besides, scaffolds will be loaded with CMs derived from Induced pluripotent stem cells (iPSCs-CMs), and will be implanted in MI models of pigs.

Delivery of FG-4592 and iPSCs-CMs through scaffolds in the damaged myocardium would promote proliferation of resident CMs and cell turnover, respectively.

Additionally, we will explore two mechanisms by which hypoxia could promote CR, remodeling of the extracellular matrix and angiogenesis mediated by angiopoietin-like 4 (Angptl-4).

This project is a necessary effort to materialize the latest advances in hypoxia and CR by combining cell therapy with a cutting-edge technology in the tissue engineering field, 3D bioprinting.