Haematopoietic stem and progenitor cells (HSPCs) do not merely generate the immune system but take an active part in its actions. “Stem cells are more adventurous than we expected,” says Ulrich von Andrian of the Harvard Medical School in Cambridge, Massachusetts who recently reported his findings in Cell.1 Far from staying put in their bone-marrow niche, small numbers of HSPCs are continually circulating throughout the body and if required, can remain in an infected tissue and quickly produce cells needed to fight the infection.

Most blood cells have relatively short life spans and are regularly replenished from HSPCs in the bone marrow. These progenitors are not restricted to the bone marrow, however, but are known to migrate from it into the blood and have previously been found in other organs, including liver, lungs and kidneys. The new work examines what happens to HSPCs that leave the bone marrow, showing that they circulate from bone marrow to tissues and back to the blood via lymph. The team also shows that HSPCs potentially have the capacity to migrate specifically into sites of infection and differentiate there to replenish local supplies of white blood cells, especially dendritic cells.

The researchers first investigated lymph, the extracellular fluid that drains from tissues and circulates via the lymphatic system to re-enter the bloodstream via the thoracic duct. The researchers found that thoracic duct lymph from mice contains a small number of HSPCs. Experiments with a variety of genetically engineered mice then showed that these lymph-borne HSPCs are indeed derived from bone marrow and have the potential to develop into white blood cells of the myeloid lineage and into T lymphocytes. The pluripotent nature of these HSPCs in vivo was confirmed by their ability to partly reconstitute the mouse haematopoietic system. From all these experiments, the researchers established that HSPCs leaving the bone marrow travel in the blood to peripheral organs such as the spleen, lungs, liver and kidneys and remain there for at least 36 hours before draining into the lymphatic system, from which they are returned to the blood and eventually to the bone marrow. This circulation route suggests that these HSPCs might be actively involved in surveying tissues for signs of infection.

Further experiments supported this theory by showing that the HSPCs can detect a common bacterial component, bacterial lipopolysaccharide (LPS). In response, HSPCs enter the infected tissues and rapidly proliferate and differentiate there into a variety of white blood cells of the myeloid lineage, especially the antigen-presenting dendritic cells, thus replenishing these cells locally when they are needed. In addition, the group found that the presence of the toxin acts to retain the HSPCs in the tissues. The normal exit of HSPCs from organs into the lymphatic system is controlled by a lipid signal. But once the cells encounter LPS, the tissue-exit signal is blocked, retaining them in the infected tissue.

It is too early to tell what the clinical relevance of this work will be, but the group hopes to start examining how the trafficking pattern of HSPCs is correlated with pathological conditions.