Scientists have generally viewed hematopoietic stem cells (HSCs) as having the singular role of remaining in the bone marrow until called upon to replenish blood and immune system cells.
But new research from the lab of HMS professor of pathology Ulrich von Andrian, published in the Nov. 30 Cell, suggests that HSCs’ biological role is far more versatile and dynamic. He and his colleagues have found that these cells can travel from the bone marrow, through the blood, to visceral organs, where they reconnoiter for pathogenic invaders. Upon encountering the enemy, they differentiate locally into whatever myeloid lineages are needed to mount a defense.
“This process changes the way we look at blood stem cells,” said von Andrian.
For almost five decades scientists have known that a fraction of HSCs sometimes migrate from the bone marrow into the bloodstream. And while scientists have observed this phenomenon, they have not known exactly why or what sort of itinerary the cells follow once in the blood.
To explore these questions, a group in von Andrian’s lab, led by postdoctoral researcher and cardiologist Steffen Massberg, extracted lymph samples from the thoracic duct of experimental mice. A major component of the lymphatic system, the duct routes excess fluids accumulating in the organs into the circulation.
After screening large samples of thoracic fluid, the researchers discovered an extremely small population of cells that, after rigorous testing, behaved identically to blood stem cells. Further tests, which involved mice genetically engineered so their blood stem cells could be detected through fluorescent microscopy, revealed that these cells were also scattered throughout visceral organs such as the liver, heart, and lung.
“Taken altogether, a picture developed suggesting that these cells migrated from the marrow and into the circulation, where they would then leak out and enter the tissue,” said Massberg. “After that, the thoracic duct would empty them back into the circulation, where they could reenter the marrow. But the question was, why? What exactly are they doing?”
The group found that the stem cells remain in the tissue for 36 hours before exiting into the thoracic duct. This suggested that the cells were conducting some kind of surveillance. To test this, Massberg and colleagues injected a bacterial endotoxin into the mouse tissue. Within a matter of days, clusters of specialized immune cells formed in the infected areas.
“Typical immune responses deplete local specialized immune cells,” said Massberg. “It appears that the hematopoietic stem cells initiate an immune response and replenish these specialized immune cells. It’s a way of sensing local environmental disturbances and responding locally.”
Ultimately, the researchers identified the molecular mechanism that explains these data.
After residing for a while in the organ tissue, the stem cells receive a lipid signal that enables them to exit into the thoracic duct. But when receptors on the stem cell surface that detect the pathogens become active, the cell’s ability to receive the lipid signal is blocked. The stem cells get stuck in the tissue, where they are then triggered to differentiate into a variety of immune cells.
“That stem cells are actually a part of the immune system, rather than just giving rise to it, is a very provocative idea,” said von Andrian, the Edward Mallinckdrot Jr. professor of immunopathology at HMS. The researchers are now looking for ways that other common diseases, like cancer, might exploit this process.
