Reprogramming of Smooth Muscle Cells May Facilitate Blood Vessel Repair

Microscopic image of human heart muscle

When a blood vessel is damaged, whether from tissue trauma or mechanical intervention such as coronary angioplasty, many of the endothelial cells (ECs) that line the vessel wall can be stripped away. ECs are notoriously slow to regenerate. Vascular smooth muscle cells (SMCs), which proliferate more quickly, often form scar tissue that can lead to restenosis and major adverse cardiovascular events. Cardiovascular researchers have been trying without much success to reprogram other cell types to repair and reendothelialize damaged vessels.

Now, researchers at Brigham and Women’s Hospital have published a proof-of-principle study showing vascular SMCs themselves can be transformed into ECs. Michael G. McCoy, PhD, a research fellow in the Division of Cardiovascular Medicine at the Brigham, Mark W. Feinberg, MD, a cardiologist in that division, and colleagues describe their approach in The FASEB Journal.

Background

The research team built on a previously proposed idea of reprogramming cells by targeting microRNAs, which are noncoding RNAs that repress the translation of messenger RNA. MicroRNAs have profound regulatory effects on cell proliferation, differentiation, and function.

What’s more, numerous microRNAs expression profiles are tied to specific tissues and cell populations. For example, EC microRNAs have key roles in the formation of blood vessels and are frequently dysregulated in vasculoproliferative diseases such as atherosclerosis or peripheral artery disease. Vascular SMCs express their own unique microRNA transcripts, including two called miR-143 and miR-145 that contribute to the functionality of those cells.

Several recent studies have demonstrated microRNA communication between ECs and SMCs. That is, each of the cell types can change the other’s behavior in response to physiological changes. Even more intriguing, a report in BMB Reports showed that microRNA reprogramming is critical to the transformation of ECs into SMCs.

The Protocol

The Brigham researchers developed a novel protocol for transforming a population of SMCs into endothelial-like cells. The steps were:

  1. Identified several microRNA transcripts (miR-143-3p and miR-145-5p inhibitors; miR-146a-5p and miR-181b-5p mimics) as potential targets based on their expression in SMCs and ECs, respectively
  2. In endothelial growth media, transfected human coronary artery SMCs with the transcripts of interest and expanded the transfected cells
  3. Sorted out cells that were positive for intercellular adhesion molecule–1 (ICAM-1), a marker of ECs

Validating the Protocol

At multiple scales, the induced ECs were transcriptionally, phenotypically and functionally similar to other ECs. In fact, they were more similar to ECs than the SMCs from which they were derived in all analyses including blood vessel formation and differentiation.

Furthermore, they found in a mouse model of ischemia that induced ECs were more effective than conventional ECs at restoring blood flow.

Looking Ahead

The miR-143/145 cluster is highly enriched in vascular SMCs, particularly in cardiac and aortic tissues. The novel approach to therapy could theoretically improve clinical outcomes in multiple cardiovascular diseases associated with endothelial injury or dysfunction, including myocardial infarction.

An important next step that the team is currently working on is to determine whether cardiac SMCs can be recruited and ECs can be generated using direct in vivo methods.

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