PhyCaR · Pseudohypoxia-mediated cardiac regeneration
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-02-14 → 2024-02-13
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Pseudohypoxia-mediated cardiac regeneration
Acute myocardial infarction (MI) leads to loss of heart tissue, tissue scarring associated with fibrosis, dysfunction, and heart failure. The pathophysiological basis of heart failure after MI in humans lies in the heart's inability to regenerate. Although it has been shown that adult cardiomyocytes (CMs) perform mitosis, their proliferation rate is extremely low for restoring normal cardiac function. It has been demonstrated that the hypoxic microenvironment (low oxygen levels) of fetal CMs drives their proliferation, and that exposure to hypoxia in adult mice with MI promotes cardiac regeneration. In both cases, the effects of hypoxia were mediated by a HIF-1α, a protein that participates in adaptation to low oxygen levels. Although hypoxia has been proposed as a treatment to promote cardiac regeneration, its systemic and adverse effects on other organs limit its clinical use. Interestingly, a condition that mimics the hypoxia (pseudohypoxia) can be pharmacologically achieved using drugs such as Roxadustat (also known as FG-4592). Roxadustat prevents the degradation of HIF-1α and consequently promotes its function. In this context, we hypothesized that the generation of a pseudohypoxic condition induced by Roxadustat in the infarcted zone promotes cardiac regeneration by inducing CMs proliferation. To target and localize the effect of this drug, we proposed implanting a biomaterial in the infarcted heart with the capacity to conjugate Roxadustat and release it gradually. The results of this project would have a significant impact on the field of cardiac regeneration, since it is the first time that pharmacological hypoxia localized in the infarct area would be generated and studied. The validation of our hypothesis also presents a unique opportunity to propose pseudohypoxia as a therapeutic alternative to restore cardiac function after MI.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE · L'Hospitalet De LlobregatCoordinatorSpain
Links
- View on CORDIS
- DOI: 10.3030/101027429
- https://idibell.cat/recerca/area-medicina-regenerativa/programa-de-medicina-regenerativa/potencia-de-cellules-mare/
Data: CORDIS, © European Union