Singapore - The secretions of stem cells

Exosomes secreted from mesenchymal stem cells help to increase the number of regulatory T cells and prevent skin graft rejection in mice.

Tiny vesicles secreted by mesenchymal stem cells can modulate the immune system and prevent the rejection of grafted tissue

Mesenchymal stem cells (MSCs) can be extracted from many different types of tissues and are currently used in clinical trials for a range of conditions, including autoimmune diseases. Now, a team of researchers led by Sai Kiang Lim at the A*STAR Institute of Medical Biology in Singapore has demonstrated that small vesicles secreted by MSCs, called exosomes, can exert anti-inflammatory effects on immune cells in tissue culture and also in mice that have received skin transplants¹.

Exosomes contain a variety of proteins and other factors from their originating cells. Previous studies have shown that MSC-derived exosomes protect heart tissue, prompting Lim and colleagues to investigate whether MSC exosomes could have an effect on immune cell function. The researchers isolated MSC exosomes but found that they did not have a direct effect on the proliferation of lymphocytes — a type of white blood cell — taken from the spleen. However, because lymphocyte function is steered by monocytes, another type of white blood cell, the researchers decided to further investigate whether MSC exosomes could activate monocytes instead. They discovered that MSC exosomes reduced the expression of pro-inflammatory factors and increased the expression of anti-inflammatory factors in monocytes.

Toll-like receptors on immune cells are proteins that initiate the immune response following activation by many different factors, including one found in MSC exosomes called fibronectic 1 (FN1). By blocking FN1 with an antibody, the researchers were able to reduce the ability of MSC exosomes to activate monocytes.

When Lim and colleagues exposed the exosome-treated monocytes to developing T cells, a type of lymphocyte, the cells matured into regulatory T (T_reg) cells — a cell type that suppresses the immune system. The findings suggest that MSC exosomes probably act directly on monocytes, which can then modulate lymphocyte maturation and function.

As a result of their immunosuppressive properties, T_reg cells can help to prevent the rejection of skin grafts by the immune system. To test whether MSC exosomes could facilitate the process, the researchers grafted skin onto mice, and then treated some of the grafted mice with MSC exosomes. Rejection of the grafted skin was delayed by a few days in the exosome-treated mice compared to normal mice, probably due to the higher levels of T_reg cells in the exosome-treated mice.

“Our findings suggest that MSC exosomes could be used to alleviate diseases that have a dysfunctional immune component, such as lupus, psoriasis and sepsis,” explains Lim. “A*STAR is currently funding the clinical development of MSC exosomes,” he says.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Bioprocessing Technology Institute

Reference

1. Zhang, B., Yin, Y., Lai, R. C., Tan, S. S., Choo, A. B. H. & Lim, S. K. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells and Development 23, 1233–1244 (2014). | article