Stem Cell-derived Tiny Vesicles Lessened Fibrosis, Inflammation

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by Marta Figueiredo PhD |

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Under-the-skin treatment with tiny vesicles produced by mesenchymal stem cells significantly lessened skin abnormalities and scarring, while reducing markers of disease and inflammation, in a mouse model of scleroderma, a study showed.

Notably, these beneficial effects — similar to those of treatment with the bone marrow-derived mesenchymal stem cells (BMSCs) themselves — were associated with vesicle-derived microRNAs (miRNAs), which are short RNA molecules that regulate gene activity and target major disease-associated signaling pathways.

These findings suggest that tiny vesicles from BMSCs result in similar effects to their parent cells and that they may represent a safe, easier-to-produce-and-store approach for the treatment of scleroderma, the researchers noted.

The study, “BMSC-derived extracellular vesicles intervened the pathogenic changes of scleroderma in mice through miRNAs,” was published in the journal Stem Cell Research & Therapy.

Scleroderma, also known as systemic sclerosis (SSc), is characterized by blood vessel abnormalities, increased inflammation, and tissue scarring, or fibrosis. As the disease progresses, the skin becomes progressively thicker and internal organs may become increasingly scarred.

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Mesenchymal stem cells (MSCs), which are capable of maturing into many other cell types, are gaining increasing interest as a potential therapeutic approach for a number of conditions due to their strong immunosuppressive, anti-inflammatory, neuroprotective, and regenerative properties.

Previous studies have shown that BMSCs have potent anti-fibrotic effects, and can lessen skin fibrosis and SSc-associated abnormalities in mouse models of scleroderma. Notably, MSCs may exert their effects not through their maturation into other cell types, but through tiny vesicles called extracellular vesicles.

Extracellular vesicles are naturally produced by various cell types in the body and contain molecules, such as miRNAs, that regulate several cellular processes, including immune and inflammatory responses.

These therapeutic properties, along with their small size and their ability to enter cells easily and avoid cells’ natural degradation processes, make extracellular vesicles strong potential therapeutic agents.

Compared with their parent cells, extracellular vesicles have several advantages, such as being simpler to produce and store, and having easier quality control procedures. They also have shown safety in animal models and in clinical trials for diabetes and other diseases.

Now, a team of researchers at Tongji University, in China, evaluated the effects of treating a mouse model of scleroderma with either BMSCs or BMSC-derived extracellular vesicles.

Both treatments, as well as a salt solution (as a control), were administered to mice through an under-the-skin injection, and their skin was analyzed two weeks later.

Results showed the two treatments resulted in similar benefits, significantly reducing skin thickening, abnormal structure, and fibrosis, as well as the number of inflammatory cells, relative to the control solution.

Further analysis revealed that the vesicles’ effects were caused by the miRNAs they carried — such as mir-21a, mir-143, mir-27b, mir-29a, and let-7 — as these were found to regulate signaling pathways involved in the growth and maturation of cell types involved in fibrosis and in fibrosis-related processes, such as TGF-beta and Wnt pathways.

Both those signaling pathways “have been found to promote each other to induce fibrosis in SSc,” the researchers wrote.

Notably, treatment with BMSC-derived extracellular vesicles was associated with significant drops in pro-fibrotic and pro-inflammatory molecules and cells in the animals’ skin to levels and numbers comparable to healthy mice.

These findings suggest that BMSC-derived extracellular vesicles might lessen skin scleroderma “by regulating the [TGF-beta] and WNT pathways as well as the inflammatory response,” the team wrote.

As such, these vesicles “could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy,” the scientists added.