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

ABSTRACT: Extracellular matrix remodeling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Such remodeling is multifaceted including changes to biochemical composition, architecture, and mechanics, clouding our understanding of how and which extracellular matrix properties contribute to a dysfunctional state. Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid that independently presents two distinct matrix properties, ligand presentation and stiffness, to cultured cells in vitro, allowing for the identification of their specific roles in cardiac aging. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, while 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 remodeling, and senescence. Importantly, we show that ligand presentation of young extracellular matrix can outweigh profibrotic stiffness cues typically present in aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent aging dysfunction and promote rejuvenation.

ORGANISM(S): Mus musculus

PROVIDER: GSE289885 | GEO | 2025/04/25

REPOSITORIES: GEO

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Project description:Despite efforts to mature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for disease modeling and high throughput screening, cells remain immature and may not reflect adult biology. Recent advancements utilize electro-mechanical and paracrine stimulation to functionally mature cardiomyocytes, but the resulting engineered constructs continue to lack a microenvironment conducive to electrical signal propagation and maturity. Conductive polymers are attractive candidates to facilitate electrical communication between gaps in sparse hPSC-CM clusters or between hPSC-CMs to repair conduction defects. To create a conductive polymer platform for improved electrical signal propagation between hPSC-CMs and achieve electrical maturity, we electrospun poly(3,4-ethylendioxythiophene):polystyrene sulfonate (PEDOT:PSS) blended with 8% (w/v) poly(vinyl alcohol) (PVA). Matrix fiber structure remained stable over 4 weeks in buffer, stiffness remains near cardiac stiffness in vivo, and electrical conductivity scaled with PEDOT:PSS concentration. When fibroblasts were added to fibers, cells had higher initial attachment to PEDOT:PSS compared to PVA-only scaffolds, and after 5 days, over 90% of fibroblasts remained viable on PEDOT:PSS scaffolds compared to PVA-only scaffolds. Electrically excitable hPSC-CMs cultured on conductive substrates exhibited an upregulation of cardiac and muscle-related genes as opposed to non-conductive substrates. These cells further displayed increased desmoplakin (DP) localization on conductive scaffolds, indicating an improvement in the mechanical stability of our hPSC-CMs. Sarcomere organization also scaled with increasing PEDOT:PSS concentration, even in sub-monolayer cell densities, suggesting that improved organization of the contractile machinery in these cells was due to the electrical condition of the matrix. Calcium handling indicated higher calcium flux with a shorter time to peak, further suggesting improved electrical maturity, even when sub-confluent. Taken together, these data suggest that PEDOT:PSS/PVA scaffolds are stable, of a stiffness relevant to cardiomyocytes, and supportive of electrical coupling even in the absence of a monolayer, which may improve cardiac disease modeling and drug development.

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

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