HGPS is a rare genetic disorder caused by a mutation in the LMNA gene that leads to the production of progerin, an abnormal form of Lamin A that drives accelerated aging. Although the disease affects multiple organs, its most severe consequences occur in the cardiovascular system, where patients develop progressive vascular and cardiac dysfunction and often die during their early teenage years. Previous disease models have largely focused on cardiomyocytes alone, limiting the ability to investigate interactions between the diverse cell types that contribute to cardiac pathology.

To address this challenge, researchers generated engineered heart tissues using cardiomyocytes and epicardial cells derived from induced pluripotent stem cells obtained from an HGPS patient and healthy parental controls. The epicardial cells were incorporated into a three-dimensional tissue platform and maintained in long-term culture. Within the engineered tissues, these epicardial cells differentiated into cardiac fibroblasts and vascular smooth muscle cells, thereby recreating a more representative cardiac microenvironment. Compared with tissues composed solely of cardiomyocytes, epicardium-integrated tissues exhibited improved tissue compaction and stronger contractile performance, highlighting the importance of cellular diversity in constructing functional heart models.

As the tissues matured, hallmark features of HGPS gradually emerged. Progerin accumulation became detectable after extended culture and was observed in the patient-derived tissues but not in control samples. This delayed appearance reflects the progressive nature of the disease and mirrors the gradual development of symptoms in patients. The model therefore enabled researchers to capture disease-associated changes as they unfolded within a multicellular human cardiac tissue environment.

Comprehensive molecular analyses revealed substantial differences between HGPS and control tissues. Gene expression profiling showed activation of pathways associated with oxidative stress, fibrosis, atherosclerosis, apoptosis, hypertrophy, extracellular matrix remodeling, and transforming growth factor-β signaling, all of which have been linked to cardiovascular aging and HGPS pathology. At the same time, genes involved in mitochondrial function were downregulated, indicating impaired cellular energy metabolism. DNA methylation analysis further identified disease-associated epigenetic alterations, including differential methylation of genes linked to cellular stress responses, mitochondrial function, apoptosis, and cardiovascular regulation.

Importantly, these molecular signatures were accompanied by functional abnormalities. Over time, HGPS tissues showed a diminished ability to respond to electrical pacing and exhibited slower spontaneous beating than control tissues. These findings suggest that disease-associated molecular remodeling eventually manifests as impaired tissue function, consistent with cardiac conduction and rhythm abnormalities associated with HGPS.

Beyond its relevance to HGPS, this study demonstrates the value of incorporating epicardium-derived cell populations into engineered heart tissues. Because epicardial cells give rise to fibroblasts and vascular smooth muscle cells that actively influence cardiac structure and signaling, their inclusion enables more accurate modeling of complex cardiovascular diseases. The platform may therefore serve as a valuable tool for uncovering mechanisms that drive cardiac aging, identifying therapeutic targets, and evaluating candidate therapies in a human-based system. More broadly, the approach establishes a foundation for developing increasingly sophisticated engineered tissues capable of modeling a wide range of cardiovascular disorders and supporting future regenerative medicine applications.

• doi: 10.1088/1758-5090/ae8eb5