New 3D Cell Culture Model Allows Study of Arterial Wall Thickening in PAH

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by David Melamed, PhD |

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A team of researchers have used 3D cell culture technology to develop a model that replicates processes involved in pulmonary arterial hypertension (PAH), allowing them to more carefully analyze the thickening of arterial walls that occurs in patients.

Their findings were detailed in the study, “3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension,” published in the journal Frontiers in Bioengineering and Biotechnology.

In PAH, the cells that line the walls of pulmonary arteries divide at an increased rate, progressively thickening the arterial walls. This causes the arteries themselves to narrow, which restricts the flow of blood and oxygen through the body, and ultimately can lead to heart failure and other symptoms.

These cells, called pulmonary arterial smooth muscle cells (PASMCs), have been studied using 2D cell culture techniques in the lab, but researchers have not been able to model the arterial wall thickening in these samples.

To address this, a team of researchers in Japan sought to develop a 3D model of arterial walls to investigate the thickening process more closely and to potentially aid in the development of treatments to alleviate this symptom of PAH.

“Given the importance of vascular medial thickening in the pathogenesis of PAH, novel therapeutics targeting this process might be beneficial in improving disease outcomes in PAH patients,” Mitsunobu Kano, PhD, a professor at Okayama University and co-supervisor of the study, said in a press release. “The lack of in vitro models that recapitulate vascular medial thickening led us to establish a new model to study this disease.”

They used a method they previously had established in a study modeling pancreatic cells to generate a 3D model of the arterial walls with a similar thickness to that of the human body.

Using PASMCs derived from patients with PAH, the researchers generated a 3D structure with four to six layers of cells and a thickness between 20 and 30 micrometers.

This model allowed researchers not only to study the process of thickening, but how other factors may influence the thickening.

One such factor is a protein known to stimulate PASMC thickening, called platelet-derived growth factor (PDGF). When researchers increased the level of PDGF in the 3D model, they observed an increase in the thickening.

“We found that PDGF induced the proliferation of PASMCs and increased the thickness of the 3D tissues,” Kano said.

They also found that imatinib, an inhibitor of PDGF that is approved for cancers and is being developed in nebulizer form for PAH, decreased the thickening effect caused by PDGF activity.

From those studies, the researchers recognized this technique could be used as a tool to investigate how potential treatments indicated for PAH influenced the thickening of the cells in the 3D model.

To assess the usefulness of the 3D model in preclinical research, they used three medications approved for PAH — Tracleer (bosentan), Adcirca (tadalafil), and MRE-269, the active metabolite of Uptravi (selexipag) — to investigate how they affected arterial wall thickening in the model.

These three therapies were chosen because they have unique molecular mechanisms for reducing arterial wall thickness.

All three were found to reduce the thickening in the 3D model, with Tracleer and Adcirca showing a greater reduction than MRE-269.

According to the researchers, their 3D model has the potential to be used in preclinical studies of any future medications developed to treat PAH.

“We thus expect that our 3D-PAH medial thickening model can potentially be used in the future to screen novel compounds for their ability to suppress medial thickening for use against PAH,” they concluded.