Stem cell-Ofev combo eased lung scarring in mice

The experimental pulmonary fibrosis treatment also promoted lung tissue repair

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A handful of rodents cluster together, with one eating a food pellet.

Treatment with mesenchymal stem cells (MSCs) bound to tiny vesicles loaded with Ofev’s active ingredient reduced lung inflammation and scarring while  promoting lung tissue repair in a mouse model of pulmonary fibrosis (PF), a study has shown.

This combination strategy worked better than Ofev alone in both young and aged mice, suggesting it could lead to therapies for patients who do not respond well enough to available medications. It’s an “inspiration for the design of PF therapies, especially for treating aged patients,” the researchers wrote.

The study, “Nanoengineered mesenchymal stem cell therapy for pulmonary fibrosis in young and aged mice,” was published in Science Advances.

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The lung scarring (fibrosis) that marks PF is the result of alveolar type 2 (AT2) cell injury and fibroblast overactivation and maturation into myofibroblasts — the main cellular drivers of lung fibrosis that produce excessive amounts of extracellular matrix (ECM) molecules.

AT2 cells, one of the cell types that line the small air sacs responsible for gas exchange in the lungs, are involved in lung tissue repair and regeneration. ECM molecules, such as collagen, surround and support cells, but when too much is produced it can cause tissue scarring.

Anti-fibrotic medications such as Boehringer Ingelheim’s Ofev can slow PF, but they don’t work as well in older patients with severe disease. That is partly because these medications cannot effectively reach the lungs and build up to therapeutic levels.

“Therefore, it is urgent to seek an effective therapeutic strategy for treating PF in aged patients,” the researchers wrote.

Mesenchymal stem cells — stem cells that can generate a variety of other cell types — have gained increasing interest for treating PF due to their anti-inflammatory and anti-fibrotic properties.

Given that they are guided toward places of lung injury due to release of attractant factors by injured AT2 cells, and that they can mature into AT2 cells, MSCs “serve as promising delivery platforms to improve lung-targeting specificity,” the researchers wrote.

Now, a team led by researchers in China came up with the idea of using MSCs to deliver Ofev to target lung cells.

Active ingredient in Ofev is nintedanib

They collected MSCs from fat tissue of healthy rats and attached them to tiny fatty vesicles, called liposomes, loaded with nintedanib, which is Ofev’s active ingredient.

Nintedanib-laden liposomes were coated with type 1 collagenase, an enzyme that breaks down collagen, and FAP target peptide, a small protein that would help guide the tiny vesicles toward overactive fibroblasts.

In order to “glue” the liposomes onto MSCs, the vesicles were coated with another small protein, called A6 peptide, that binds to the CD44 receptor protein on the surface of MSCs.

To test how well these liposome-bound MSCs would home in on damaged lungs, the researchers turned to a mouse model of PF, in which a mice’s lungs are exposed to a toxic chemical called bleomycin. MSCs, liposomes, and activated fibroblasts were tagged with different fluorescent molecules to monitor their location over time.

The team found that after being injected directly into the bloodstream of these mice, the MSCs indeed traveled to the lungs. Liposomes alone were unable to travel there, so having them glued onto the MSCs got them delivered to the right place.

Once they reached the lungs, the liposomes began to loosen from the MSCs. This happened in response to MMP-2, an enzyme overly present in fibrotic lungs that can cut the bond between A6 peptide and CD44.

Some hours later the team could see that the nintedanib-loaded liposomes were highly co-localized with overactive fibroblasts, suggesting that the tiny vesicles could “efficiently [break down] collagen fibers and target fibroblasts,” the researchers wrote.

Assessing effects in younger, older mice

Next, the researchers evaluated the approach’s therapeutic effects in young (2-month-old) and aged (16-month-old) mice.

Administered directly into the stomach, Ofev alone slowed lung scarring in young mice, but its action “was limited in aged mice mainly because its low delivery efficiency to the lungs in the presence of compact collagen fibers, and the impotence of the [repair] of injured [AT2 cells],” the researchers wrote.

However, when nintedanib was laden on liposomes glued to MSCs, it was delivered directly to fibroblasts. So, even in aged mice, it suppressed fibroblast overactivation and reduced collagen buildup, and to a greater extent than MSCs alone.

Still, the MSCs themselves were found to play a role in slowing the progression of lung fibrosis.

In both young and aged mice, they toned down the levels of the inflammatory molecules TNF-alpha, IL-1beta, and IL-6. Moreover, in aged mice, they matured into AT2 cells, as seen under a microscope in slices of the lungs.

As a result, the combination of MSCs and nintedanib-laden liposomes helped rebuild the damaged lungs of older mice with severe scarring.

The new approach “exhibited rapid lung targeting and persistent accumulation within fibrotic lungs,” the team wrote, with the type 1 collagenase on nintedanib-loaded liposomes improving the “accumulation of these nanoparticles” inside cells.

“Furthermore, MSCs [matured] into [AT2 cells] to participate in reestablishing lung function,” they added.

Given that “MSCs and liposomes have been widely used in clinic,” the researchers wrote, the combination of MSCs and nintedanib-laden liposomes “provides inspiration for the design of PF therapies, especially for treating aged patients.”

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