Article Impact Level: HIGH Data Quality: STRONG Summary of Bioactive Materials, 45, 181–200. https://doi.org/10.1016/j.bioactmat.2024.11.018 Peng Tang et al.
Points
- The study developed a method to transdifferentiate fibroblasts into valvular endothelial cell-like cells (VECs) without using induced pluripotent stem cells (iPSCs), avoiding tumorigenesis risks.
- Researchers combined soluble chemicals, cytokines, and substrate stiffness modulation to convert fibroblasts into iAECs (mouse) and hiVECs (human), which expressed VEC-specific markers such as NFATC1 and displayed functional endothelial characteristics.
- The engineered cells maintained VEC functionality in vitro and in vivo, successfully integrating onto decellularized porcine aortic valves and remaining viable for 60 days in immune-compromised rats without forming tumors.
- Unlike iPSCs, which showed a risk of teratoma formation due to residual pluripotency markers, the direct fibroblast-to-VEC transdifferentiation method proved safer and more reliable.
- This innovative approach offers a promising pathway for creating functional, autologous tissue-engineered heart valves and has potential applications in broader tissue engineering contexts.
Summary
This study addresses the challenges of generating differentiated cells for tissue engineering, particularly valvular endothelial cells (VECs), without the risk of tumorigenesis often associated with induced pluripotent stem cells (iPSCs). By using a novel combinatorial strategy involving soluble chemicals, cytokines, and substrate stiffness modulation, the researchers were able to transdifferentiate mouse embryonic fibroblasts into induced aortic endothelial cell-like cells (iAECs) and human primary adult fibroblasts into induced valvular endothelial cell-like cells (hiVECs) without the need for reprogramming into iPSCs. These cells expressed VEC-specific markers such as NFATC1 and demonstrated functional characteristics typical of endothelial cells in culture.
The functionality of the generated iAECs and hiVECs was validated both in vitro and in vivo. The cells were seeded onto decellularized porcine aortic valves, and their integration and functionality were tested in a bioreactor setup and in vivo using nude rats. In vitro, these cells maintained their VEC characteristics. In vivo, they remained viable and expressed endothelial markers for up to 60 days post-implantation in the abdominal aorta of immune-compromised rats. In contrast, iPSCs, when differentiated into VEC-like cells, expressed pluripotency markers such as Nanog in a small subpopulation, which led to teratoma formation in SCID mice, highlighting the potential risks of using iPSCs.
This research demonstrates a safer and more efficient method for generating endothelial cells directly from fibroblasts, bypassing the use of viruses or the reprogramming step into iPSCs. The successful creation of functional tissue-engineered aortic valves from iAECs and hiVECs offers a promising strategy for developing autologous, safe, and effective treatments for heart valve diseases. The findings suggest that this approach could be expanded for other types of tissue engineering.
Link to the article: https://www.sciencedirect.com/science/article/pii/S2452199X24005024
References Tang, P., Wei, F., Qiao, W., Chen, X., Ji, C., Yang, W., Zhang, X., Chen, S., Wu, Y., Jiang, M., Ma, C., Shen, W., Dong, Q., Cao, H., Xie, M., Cai, Z., Xu, L., Shi, J., Dong, N., … Wang, N. (2025). Engineering aortic valves via transdifferentiating fibroblasts into valvular endothelial cells without using viruses or iPS cells. Bioactive Materials, 45, 181–200. https://doi.org/10.1016/j.bioactmat.2024.11.018
