Endothelial cell direct reprogramming: Past, present, and future

Abstract

Ischemic cardiovascular disease still remains as a leading cause of morbidity and mortality despite various medical, surgical, and interventional therapy. As such, cell therapy has emerged as an attractive option because it tackles underlying problem of the diseases by inducing neovascularization in ischemic tissue. After overall failure of adult stem or progenitor cells, studies attempted to generate endothelial cells (ECs) from pluripotent stem cells (PSCs). While endothelial cells (ECs) differentiated from PSCs successfully induced vascular regeneration, differentiating volatility and tumorigenic potential is a concern for their clinical applications. Alternatively, direct reprogramming strategies employ lineage-specific factors to change cell fate without achieving pluripotency. ECs have been successfully reprogrammed via ectopic expression of transcription factors (TFs) from endothelial lineage. The reprogrammed ECs induced neovascularization in vitro and in vivo and thus demonstrated their therapeutic value in animal models of vascular insufficiency. Methods of delivering reprogramming factors include lentiviral or retroviral vectors and more clinically relevant, non-integrative adenoviral and episomal vectors. Most studies made use of fibroblast as a source cell for reprogramming, but reprogrammability of other clinically relevant source cell types has to be evaluated. Specific mechanisms and small molecules that are involved in the aforementioned processes tackles challenges associated with direct reprogramming efficiency and maintenance of reprogrammed EC characteristics. After all, this review provides summary of past and contemporary methods of direct endothelial reprogramming and discusses the future direction to overcome these challenges to acquire clinically applicable reprogrammed ECs.

Keywords: Cardiovascular disease; Cell therapy; Direct reprogramming; Endothelial cells; Neovascularization; Regenerative medicine.

Figure 1.

Methods of direct endothelial reprogramming with various source cell types. Fibroblasts, human adipose-derived stem cells (hADSCs), mesenchymal stem cells (hMSCs), and human amniotic fluid-derived cells (hACs) were reprogrammed into endothelial cells (ECs). A. The diagram showing origin of the source cells. B. The graphic showing source cell types, reprogramming methods, and target cell. Alphabets from A-N indicate studies as referred from Table 1.