A research team from Boston Children Hospital’s Stem Cell Research Program has provided the first direct glimpse into how blood stem cells take root in the body to generate blood – with the help of a see-through zebrafish and direct visualization. The dynamic imaging system offers several clues for improving bone-marrow transplants in patients with cancer, severe immune deficiencies, and blood disorders, and for helping those transplants thrive.
“Our direct visualization gives us a series of steps to target, and in theory we can look for drugs that affect every step of that process,” said senior investigator, Leonard Zon, MD, director of the Stem Cell Research Program and professor of stem cell and regenerative biology at Harvard Medical School.
Using time-lapse imaging of naturally transparent zebrafish embryos and “tagging” the stem cells green, researchers were able to reveal how stem cells find the “niche” where they begin to create blood in the body’s circulation. On arrival in its niche, the newborn blood stem cell attaches itself to the blood vessel wall where chemical signals prompt it to squeeze itself through the wall and into a space just outside the blood vessel.
In that space, many cells interact with and wrap around the stem cell, including endothelial cells. Dr. Zon and researchers call this process “endothelial cuddling,” ensuring that the stem cell stays in its niche. While there, stromal cells help keep the stem cell attached. The team was able to reassemble the whole process through a series of image slices. Eventually the stem cells begins dividing and ultimately colonize their future site of blood production – the kidney, in the case of the zebrafish.
Researchers also observed a similar process when they imaged mice, which makes it likely that blood stem cells behave the same way in humans.
“Stem cell and bone marrow transplants are still very much a black box — cells are introduced into a patient and later on we can measure recovery of their blood system, but what happens in between can’t be seen,” says Owen Tamplin, MD, the paper’s co-first author. “Now we have a system where we can actually watch that middle step.”
Tamplin OJ, Durand EM, Carr LA, et al. Hematopoietic stem cell arrival triggers dynamic remodeling of perivascular niche. Cell. 2015;160:241-52.