MSCs may target monocytes, macrophages to reduce fibrosis

Reduced fibrosis, inflammation, and cell death seen in MSC-treated mouse model

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Certain populations of immune monocytes and macrophages may be important targets of mesenchymal stem cell (MSC) therapy in idiopathic pulmonary fibrosis (IPF), according to a study.

In an IPF mouse model, into-the-vein MSC treatment appeared to prevent monocytes from becoming a type of macrophage thought to promote the buildup of scar tissue, or fibrosis, in IPF. Treated mice had reduced fibrosis, inflammation, and cell death than untreated mice.

The findings indicate monocytes and macrophages “play important roles in the development of pulmonary fibrosis,” the researchers wrote, noting the therapeutic effects of MSCs may, in part, be driven by the modulation of these cells.

The study, “Classical monocyte-derived macrophages as therapeutic targets of umbilical cord mesenchymal stem cells: comparison of intratracheal and intravenous administration in a mouse model of pulmonary fibrosis,” was published in Respiratory Research.

MSCs are stem cells that can give rise to virtually any other cell type. They play important roles in tissue repair and immune regulation, and are generally thought to be anti-inflammatory and anti-fibrotic.

These properties are thought to make MSCs a promising therapeutic strategy for IPF, which is supported by a growing body of preclinical evidence. MSCs obtained from the human umbilical cord seem to have particularly promising therapeutic properties.

Still, the exact mechanisms by which MSCs are therapeutic are complex and not completely understood, leading researchers in Korea to try to better understand their effects on specific immune cell types. The researchers were particularly interested in macrophages, the most abundant immune cell in healthy lungs that play key a role in clearing pathogens, or disease-causing microbes.

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MSC therapy’s effects on immune cells

While some macrophages are resident in lung tissue and support normal function, others are derived from immune monocytes that circulate in the bloodstream and travel to various tissues during inflammation.

Monocyte-derived macrophages are known to exist in two states. M1 macrophages release inflammatory molecules that help eliminate pathogens, while M2 macrophages release wound-healing anti-inflammatory molecules, but are also known to contribute to tissue remodeling and fibrosis.

Previous research suggests a shift toward an M2 balance and M2 infiltration into the airways supports the progression of IPF.

Researchers examined lung tissue from IPF patients, finding that markers of macrophages and monocytes were elevated in areas with more fibrosis than in areas with less tissue scarring.

When these monocyte-derived macrophages were stimulated in cell cultures with a pro-fibrotic molecule, they began expressing M2-like markers and to promote fibrosis, which was suppressed by MSC treatment.

The researchers generated a mouse model of IPF and treated the animals with MSCs derived from human umbilical cords. MSCs were either delivered as an into-the-vein (intravenous) injection or directly into the airways (intratracheal injection).

The treatment was therapeutic in the mouse model, leading to reduced inflammation, fibrosis, and cell death in the lungs. The number of inflammatory cells in the lungs, including macrophages, neutrophils, and eosinophils, was also reduced. The effects tended to be more prominent with intravenous delivery.

Macrophages were generally increased in the IPF model and reduced by MSC treatment. A subset of M2 monocyte-derived macrophages were particularly reduced with intravenous MSC treatment. Tissue resident macrophages weren’t affected by the treatment, however.

The M2 macrophages that were most impacted by treatment were derived from a certain population called Ly6c-positive, or classical, monocytes, experiments showed. These monocytes are known to travel to tissues during inflammatory responses, where they differentiate into macrophages specific for that tissue.

Other immune cell populations, including inflammatory T-cells, were also reduced with MSC treatment, while the proportion of regulatory T-cells, generally thought to be anti-inflammatory, was increased.

The findings suggest intravenous MSCs “may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages,” the researchers wrote, noting the relatively greater effectiveness of the intravenous administration could be related to a “more rapid and effective” targeting of circulating monocytes that later become macrophages, adding monocytes may be “one of the main targets of MSCs.”

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