Research database

Cardiac fibrosis is a maladaptive remodeling of the myocardium hallmarked by contraction impairment and excessive extracellular matrix deposition (ECM). The disease progression, nevertheless, remains poorly understood and present treatments are not capable of controlling the scarring process. This is partly due to the absence of physiologically relevant, easily operable, and low-cost in vitro models, which are of the utmost importance to uncover pathological mechanisms and highlight possible targets for anti-fibrotic therapies. In classic models, fibrotic features are usually obtained using substrates with scar mimicking stiffness and/or supplementation of morphogens such as transforming growth factor ß1 (TGF-ß1). Qualities such as the interplay between activated cardiac fibroblasts (CFs) and cardiomyocytes (CMs), or the mechanically active, three-dimensional (3D) environment, are, however, neglected or obtained at the expense of the number of experimental replicates achievable. Paracrine modulation of cardioprotective and anti-fibrotic effects to enhance myocardial repair has attracted increasing interest in the last years, with specific focus on the role of soluble factors released by stem and progenitor cells. Particularly, the stem/progenitor cell secretome – i.e. cell-secreted paracrine factors, including both soluble individual molecules and membrane-bound extracellular vesicles - has been proposed as a novel therapeutic candidate in regenerative medicine. Nanoscale cell-derived extracellular vesicles (EVs) are critical component of the stem cell secretome and have been reported as curative boosters to significantly enhance cardiac reparative mechanisms while decreasing scarring, in several preclinical models of myocardial infarction, ischemia-reperfusion injury. Notably, the secretome of human perinatal stem cells - such as the human amniotic fluid-derived stem cells or hAFSC – is enriched with bioactive EVs able to exert relevant cardioprotective and anti-fibrotic effects on murine myocardium after severe ischemic injury. However, their effect in vivo may be impaired by an uncontrolled release to the insulted region. To overcome these shortcomings, RECOVERY will engineer a fully human cardiac Organ-on-Chip (OoC) model where cardiac micro-tissues can be subjected to cyclical stretching inducing a fibrotic phenotype. The OoC device will embed online recording capabilities so to continuously monitor both the cardiac electrophysiology and the onset of fibrotic ECM deposition via electrical impedance evaluation. The cardiac OoC device will be used to validate a new method to deliver hAFSC-EVs as advanced therapy medicinal products to treat cardiac fibrosis. Particularly, injectable hydrogels based on modified natural polymers will be developed promoting an optimal controlled and sustained delivery of embedded hAFSC-EVs.