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AN INDUCED PLURIPOTENT STEM CELL-BASED MODEL TO STUDY THE MECHANOBIOLOGY OF MYOCARDIAL FIBROSIS
Francesco Niro1,2, Daniel Pereira De Sousa1,2, Jorge Oliver-De La Cruz1, Soraia Fernandes1, Stefania Pagliari1, Marco Cassani1, Vladimir Vinarsky1,2 Ece Ergir1, Giancarlo Forte1,2
- International Clinical Research Center (ICRC), St Anne’s University Hospital Brno
- Department of Biomedical Science, Faculty of Medicine, Masaryk University
Cardiac fibrosis is the consequence of chronic insults on the myocardium, and it is characterized by the abnormal accumulation of extracellular matrix (ECM). The transdifferentiation of cardiac fibroblasts (cFbs) into myofibroblasts drives pathological ECM remodeling, a process highlighted by biochemical and structural changes which compromise cardiomyocytes (CMs) contractile activity and eventually lead to heart failure [1]. Here, we adopted bioengineering tools and induced pluripotent stem cells (iPSCs) to investigate how fibrotic ECM affects the structural and functional properties of CMs.
Thus, we derived cFbs from induced pluripotent stem cells (iPSCs-cFbs) and optimized a protocol based on biochemical and mechanical stimulation to induce their transdifferentiation to myofibroblasts. Next, we obtained fibrotic ECM (dECM) by implementing a decellularization procedure of the activated iPSCs-cFbs and analyzed the pathological changes occurring during the deposition of cardiac diseased ECM. The results generated through this analysis were confirmed by studying dECM of cFbs isolated from heart failure patients and their healthy counterparts. Then, we generated iPSCs-CMs and cultured them either on healthy or fibrotic dECM. Morphological and functional analyses were implemented to study how the biomechanical properties of pathological ECM affect CMs physiology and function.
Finally, we established a 3D in vitro culture system, which entails the co-culture of isogenic iPSCs-CMs and -cFbs that better reproduces the cellular complexity and functionality of the human heart and represents a powerful tool for personalized medicine applications.
By capitalizing on this approach, we might be able to recapitulate the accumulation of fibrotic tissue occurring during heart disease and investigate the contribution of pathological ECM to the progression of heart failure.
References
[1] Frangogiannis, N.G., J Clin Invest.127(5), 1600-1612 (2017)
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