Effect of cellular and ECM aging on human iPSC-derived cardiomyocyte performance, maturity and senescence

Abstract

Cardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here, we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell (iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking stress conditions in vitro.Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.

Age related extracellular matrix and interstitial cell phenotype in pulmonary valves

“…This indicates that adult PV leaflets may be intended to undergo pathological changes. On the other hand, young PV leaflets and PVICs upregulated many physiological protective proteins/genes, like heat shock protein 90 alpha family class A member 1 (HSP90AA1, related to cellular response and recovery), SPP1 (related to bone resorption), and beclin 1 (BECN1, related to autophagy), which have been demonstrated to be beneficial for directly protecting valve cells or slowing down the pathological progression through a compensatory mechanism 36 – 39 . Balaoing et al evaluated hemostatic protein regulation in AV tissues and porcine valve endothelial cells (PVECs) with age and reported that old AV leaflets expressed more von Willebrand factor (vWF), while PVECs from the young age group had more gene expression of vWF 40 .…”

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

“…Extended culture times of PSC-CMs can improve some aspects of maturation [227], but can also increase an aging phenotype, with increased SA-β-gal activity, increased lipofuscin accumulation, and reduced mitochondrial membrane potential, which can be reversed with treatment with the antioxidant, ascorbic acid [228]. When human PSC-CMs are cultured with young, adult, or aged extracellular matrix proteins from mice, young ECM increases PSC-CM proliferation, adult ECM enhances PSC-CM function, and aged ECM produces an aging phenotype with reduced PSC-CM function and lipofuscin accumulation, increased SA-β-gal activity, and increased ROS levels [229], suggesting that extracellular factors control transitions between proliferative, quiescent, and senescent phenotypes.…”

Tunable Human Myocardium Derived Decellularized Extracellular Matrix for 3D Bioprinting and Cardiac Tissue Engineering

“…Cell-free ECM is composed of the structural proteins as well as the secreted products of the resident cells [ 44 ]. Preservation of the ECM biochemical composition is crucial since ECM provides bioactive cues that affect cell response to its environment such as proliferation, migration, and differentiation [ 21 , 26 , 45 ]. Therefore, to ensure human cardiac tissue decellularization with the preservation of ECM bioactivity, we optimized previous decellularization methods [ 46 , 47 ] and used a combination of ionic and non-ionic detergent washes.…”

“…To obtain naturally derived biomaterials recapitulating the biochemical cues in the native tissue environment, decellularization techniques have been developed and decellularized ECM (dECM) has become a preferred biomaterial for cardiac tissue engineering applications such as cardiac repair and regeneration [ 21 , 22 , 23 , 24 , 25 ]. In addition to being able to mimic the complexity of the native tissue and recreate a microenvironment with improved cell–cell connections and 3D cellular organization, the age of dECM was shown to affect cell response, thus by using dECM, the effect of age can also be introduced in the in vitro models [ 26 ]. Although dECM preserves the biochemical composition of the native tissue, it loses the mechanical and structural stability of tissue during the decellularization and digestion processes.…”