Endothelial reprogramming for vascular regeneration: Past milestones and future directions

Endothelial cells are critical mediators of health and disease. Regenerative medicine techniques that target the endothelium hold vast promise for improving lifespan and quality of life worldwide. Regenerative therapies via induced pluripotent stem cells (IPSCs) have helped demonstrate disease mechanisms, but so far, concerns regarding their function, malignant potential, and expense have limited therapeutic potential. One alternative approach is direct reprogramming of somatic cells, which avoids the pluripotent state and allows for in vivo reprogramming. Transcription factors from endothelial development have yielded essential transcription factors and small molecules that induce endothelial cell fate. Most direct cell reprogramming strategies targeting endothelial cells use ETV2, a pioneer transcription factor to specify endothelial lineage via histone-modifying enzymes. Many different types of starting cells and strategies, including lentiviral transduction, inducing innate immunity, and small molecule signaling have been leveraged for reprogramming. However, so far therapeutic benefit of these strategies remains unproven. Future research will have to solve scalability, safety, and efficacy hurdles before being ready for the clinic. However, researchers have already discovered meaningful insights into disease mechanisms and development through direct reprogramming.