Combining genome and tissue engineering for next-generation human biomimetics

This study integrates human induced pluripotent stem cell (hiPSC) biology with genome engineering to create a stable, customizable cell source for next-generation human tissue-engineered matrices (hTEMs). Researchers developed a chemically defined differentiation protocol to generate isogeneic cardiac fibroblast-like cells (iCFs) exhibiting transcriptomic and phenotypic similarity to primary human cardiac fibroblasts. Gene-editing using TALENs upregulated ECM-related proteins including elastin (ELN), fibulin-5 (FBLN5), lysyl oxidase (LOX), and LOXL1, enabling targeted modulation of collagen deposition, elastic fiber maturation, and ECM organization. Proteomics analysis revealed that edited iCF-derived hTEMs demonstrated increased core matrisome components, enhanced glycosaminoglycan and proteoglycan content, and enrichment of cardiovascular-specific ECM pathways. Biaxial mechanical testing confirmed that gene-edited constructs exhibited increased toe-region elasticity and significantly higher collagen-driven stiffness, reflecting improved fiber crosslinking and maturation. Collectively, these findings demonstrate a robust platform for engineering designer hTEMs capable of improved mechanical performance and tailored ECM composition for cardiovascular applications.