Key player in the bone-marrow protection of orally-administrated Astragalus polysaccharide RAP after entering Peyer’s patches

Radix Astragali (Huangqi), the mostly used Qi tonic in Chinese Medicine, is popularly used in combination with chemotherapy to reduce the side effects, especially bone marrow suppression. The orally dosed Radix Astragali polysaccharide (RAP) has been proved to be able to protect blood cells, bone marrow, as well as mice/human hematopoietic stem cells (HSC). While the effects have been verified, it is hard to understand the underlying mechanisms, because this macromolecule is non-absorbing and indigestible.

In our preliminary study, we discovered that RAP could quickly enter Peyer’s patches (PPs) in the small intestine via transcytosis through microfold cells (M-cells) in PPs. This delivery route was confirmed in human gut explants and shown to depend on the specific binding of RAP to the GP2 receptor on M-cells. Furthermore, RAP induced the MAPK/NFkB signaling pathways and production of cytokine IL-6 in Peyer’s patches. As we observed in vitro, both IL-6 production and the activation of MAPK/NFkB signaling pathways could be attributed to RAP’s inducing effects on dendritic cells and macrophages. RAP also increased the ratio of cytotoxic T cells and decreased the ratio of regulatory T cells in PPs. These findings suggest that RAP can activate some specific immune cells in PPs. However, how RAP affects the distant bone marrow and HSCs remains unknown.

We have detected RAP’s fluorescence signal in bone marrow under confocal micrograph in our preliminary study. It is suggested that RAP may directly contact HSCs after transported to bone marrow by some specific immune cells, which are activated by RAP in PPs, as the transporter. In addition, these activated immune cells themselves may also affect HSCs when migrated to bone marrow. Therefore, we hypothesize that these specific immune cells might be the key player in the bone-marrow protection of RAP after its entering PPs, where they are activated by RAP, and then carrying RAP or not, migrate to bone marrow and affect the HSCs.

To test this hypothesis, the current project aims to:
1) identify the antigen-presentation immune cells activated by RAP in PPs, and determine the mechanism of activation;
2) identify the activated immune cells which migrated to bone marrow with/without RAP;
3) determine the protection mechanism of RAP and/or the migrated immune cells towards HSCs.

The success of this project will help resolving the long-standing mystery of how an orally dosed polysaccharide affects immune system, and then facilitate Research & Development of polysaccharide-based new drugs.