A miRNA Cassette Reprograms Smooth Muscle Cells into Endothelial Cells

Principal Investigator: Mark W. Feinberg

Authors: Michael G. McCoy, Daniel PĂ©rez-Cremades, Nathan Belkin, Wenhui Peng, Bofang Zhang, Akm Khyrul Wara, Rulin Zhuang, Henry S. Cheng, Mark W. Feinberg
Lay Abstract

Damage to the endothelium, the innermost lining of the blood vessel, is a major contributor to the progression of cardiovascular diseases. This is because the regeneration of the endothelium is notoriously slow, and few effective therapies exist to facilitate healing of the vasculature. We hypothesized that a nearby cell source surrounding blood vessels, smooth muscle cells, could be transformed into endothelial cells with a small cassette of molecular targets. By identifying and targeting small genetic signaling networks within smooth muscle cells, we were capable of functionally transforming them into endothelial cells. Injected transformed endothelial cells restored blood flow recovery even faster than conventional endothelial cells in a mouse hindlimb ischemia model. With recent public interest and advancements in the application of RNA therapeutics, we believe this research demonstrates the potential of RNA medicine in cardiovascular disease.

Scientific Abstract

Cellular reprogramming through targeting microRNAs (miRNAs) holds promise for regenerative therapy due to their profound regulatory effects in proliferation, differentiation, and function. We hypothesized that transdifferentiation of vascular smooth muscle cells (SMCs) into endothelial cells (ECs) using a miRNA cassette may provide a novel approach for use in vascular disease states associated with endothelial injury or dysfunction. miRNA profiling of SMCs and ECs and iterative combinatorial miRNA transfections of human coronary SMCs revealed a 4-miRNA cassette consisting of miR-143-3p and miR-145-5p inhibitors and miR-146a-5p and miR-181b-5p mimics that efficiently produced induced endothelial cells (iECs). Transcriptome profiling, protein expression, and functional studies demonstrated that iECs exhibit high similarity to ECs. Injected iECs restored blood flow recovery even faster than conventional ECs in a murine hindlimb ischemia model. This study demonstrates that a 4-miRNA cassette is sufficient to reprogram SMCs into ECs and shows promise as a novel regenerative strategy for endothelial repair.

Clinical Implications
Our findings have therapeutic applications as endothelial denudation followed by neointimal proliferation and restenosis is a frequent occurrence during cardiovascular intervention. The pro-angiogenic functions of these cells may also serve as a scalable source of endothelial cells for cardiovascular diseases.

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