Fight Aging!

The creation of effective regenerative therapies for the aging heart is an area of active research and development. Cell therapies based on delivery of cardiomyocytes proved to be challenging, as just as in every other early approach to cell therapy, near all transplanted cells fail to survive. More recently researchers have engineered tissue patches made up of cardiomyocytes and supporting artificial extracellular matrix structures made of hydrogels and other materials. When such a patch is applied to injured heart tissue, it allows more of the transplanted cells to survive, resulting in the generation of healthy tissue.

The natural extracellular matrix of the heart undergoes change with age. This aging of the extracellular matrix is nowhere near as well studied as the aging of cells, yet it is considered important as a contributing factor in the age-related disruption of tissue function. Given the efforts to generate engineered tissue to repair aged hearts, there is a growing interest in better understanding the aging of the extracellular matrix and how the various signals involved might be relevant to building better tissue patches. Today's open access paper is illustrative of this line of research and development.

Hybrid hydrogel-extracellular matrix scaffolds identify biochemical and mechanical signatures of cardiac ageing

Cardiac fibroblasts (CFs) are the resident cells largely responsible for the remodelling of heart tissue and are known to be mechanosensitive. In healthy tissue, CFs largely remain in a quiescent state, but external stimuli, including biochemical, structural, and mechanical cues, are able to activate quiescent CFs, leading to their differentiation into a proto-myofibroblast phenotype and subsequently into a mature myofibroblast phenotype when these stimuli are impactful and persistent. The process of CF activation and proper myofibroblast maturation are essential for extracellular matrix (ECM) deposition and the maintenance of matrix homeostasis but can also lead to fibrosis and result in functional consequences. This is important in ageing tissues, as alterations in the ECM can be vast and multifaceted, thereby leading to the activation of CFs and subsequent aberrant tissue remodelling.

Indeed, it has been shown that myofibroblasts are more abundant in aged versus young hearts and directly induce changes to the tissue geometry. Although in vitro material systems have identified individual properties of the ECM that play distinct roles in CF function, it remains a challenge to vary these properties independently. In most scaffold platforms, tuning the mechanical properties will alter the ligands and/or architecture. A handful of novel material systems have been described that are capable of independent tunability, yet the incorporation of native ECM properties is still lacking. Thus, our understanding of the specific contributions stemming from ECM cues is currently limited. We, therefore, sought to develop a native ECM-based scaffold in which we could individually tune the mechanics and faithfully mimic the in vivo cardiac environment - both composition and architecture - allowing for the identification of ECM-specific roles in age-related CF activation, mechanosensing, matrix remodelling, and senescence.

Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties - ligand presentation and stiffness - to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling, and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.