LONDON – An international team of scientists has discovered that stem cells communicate with other cells by delivering tiny vesicles containing proteins and messenger RNA, among other things.

Although stem cell therapies are showing promising progress for the treatment of conditions such as multiple sclerosis, spinal cord injury or stroke, with encouraging results from tests in animal models and early clinical trials, the latest finding could make it possible to avoid using cells entirely.

Stefano Pluchino, university lecturer at the Wellcome-Trust Medical Research Council Stem Cell Institute in Cambridge, UK, told BioWorld Today: "We have shown how stem cells speak to other cells, such as immune system cells, using extracellular membrane vesicles. Once we have provided evidence of the function of the molecules that are trafficked in these vesicles, it is not completely unrealistic to envisage a completely stem cell-free approach to those diseases that have been treated with stem cells so far, using vesicles."

Such a method would have huge advantages, he added. "A strategy involving use of extracellular vesicles would have simplified manufacturing processes and it would facilitate standardization. In addition, it would completely eliminate the possible risk of malignant transformation in transplanted stem cells," he said.

In situations where clinicians wanted to deliver stem cells with a specific function to a patient, working with extracellular vesicles would make the function much easier to control.

Pluchino and his collaborators have published their work in the Sept. 18, 2014, issue of Molecular Cell in a paper, titled "Extracellular vesicles from neural stem cells transfer IFN-gamma via lfngr1 to activate Stat1 signalling in target cells".

Earlier work by other teams had already established that transplanted stem cells were able to communicate with the host by secreting cytokines (chemical messengers) and/or growth factors, and had identified that extracellular vesicles might play a role.

Extracellular vesicles are small particles bound by a lipid bilayer containing transmembrane proteins and which contain a mixture of components derived from the cytosol of the cells from which they came.

Pluchino and his team set out to study neural stem cells – currently being used in animal model studies and clinical trials to treat conditions such as stroke – in order to find out what sort of communications these cells made via extracellular vesicles. They also wanted to know which molecules were involved in that communication, and what effect was on the target cells.

"Our study revealed that these naturally occurring nanoparticles contain a number of molecular regulators, including proteins, messenger RNAs and transcription factors," Pluchino said.

The researchers decided to focus on inflammation and those molecules involved in inducing or suppressing inflammation, especially interferon gamma and the signaling pathway downstream of interferon gamma.

Their experiments showed that neural stem cells expressed receptors for pro-inflammatory cytokines. "We propose that these receptors allow these cells to sense an inflammatory environment, with the presence of inflammatory cytokines such as interferon gamma, thus activating a receptor-specific signaling response in the cells," Pluchino said. "And, as a result of this exposure to inflammatory cytokines, the cell is able to regulate a specific trafficking of messenger RNA via the production of extracellular vesicles. In this way, the vesicles would mimic the response of the parental stem cell to its environment."

Other results showed that a highly specific pathway of gene activation is triggered in neural stem cells by interferon gamma, and that this protein also binds to a receptor on the surface of vesicles. When the vesicles are released by the neural stem cells, they adhere to and are taken up by target cells. As a result, the target cells receive proteins and nucleic acids that help them to repair themselves; in addition, the target cells receive interferon gamma on the surface of the vesicles, which triggers further gene activation within the target cells.

The team is currently working on engineering stem cells in order to make them produce specific types of vesicles that are able to target particular sites or tissue types, such as brain tissue.

"We are already working on vesicles that are specifically enriched in molecules that we believe would be functional in reducing the activation of immune cells," Pluchino said. "We want to compare stem cell-based approaches with vesicle-based therapeutics, using in vivo animal models for multiple sclerosis, spinal cord injury and stroke, before progressing to clinical trials eventually."