Work

Cardiac regeneration revisited: Enhanced cardiomyocyte differentiation and repair through composite microenvironments and small molecules

Year: 2025

Type: article

Abstract: BACKGROUND: The generation of mature, functional cardiomyocytes from human pluripotent stem cells (hPSCs) remains a major challenge in cardiac regenerative medicine. While fibronectin and Matrigel individually support cardiomyocyte differentiation, their combined potential, particularly when integrated with temporally optimized small-molecule modulation of developmental signaling pathways, has not been systematically investigated. METHODS: We engineered a biomimetic fibronectin-Matrigel composite extracellular matrix and applied precisely timed small-molecule modulation of key signaling cascades to drive efficient cardiomyocyte differentiation from hPSCs. Differentiation efficiency, structural organization, and functional maturation were assessed using immunocytochemistry, qRT-PCR, sarcomere imaging, and contractility assays. RESULTS: This composite microenvironment significantly enhanced cardiac-specific marker expression, promoted highly organized sarcomere architecture, and improved contractile function, producing a maturation profile closely resembling native myocardium. Moreover, the platform supported long-term culture with sustained structural and functional stability and consistently outperformed fibronectin-only or Matrigel-only substrates. CONCLUSIONS: Our study presents a robust, scalable, and mechanistically informed platform that synergistically integrates ECM engineering with targeted signaling pathway modulation. By combining fibronectin-Matrigel composites with small-molecule-directed differentiation, this strategy provides a powerful tool for cardiac tissue engineering, disease modeling, high-throughput drug screening, and regenerative therapies, representing a significant step toward clinically relevant cardiac repair.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118642

Authors: Manizheh Azhdari, Shahram Rabbani, Nader Tanideh, Safieh Boroumand

Institutions: Shiraz University of Medical Sciences, Maastricht University Medical Centre, Maastricht University, Tehran Heart Center, Tehran University of Medical Sciences

Language: English

Topic: Pluripotent Stem Cells Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,610