Why blood stem cells are in our bones: Evolutionary observation may inform better bone marrow transplants

blood stem cells melanocytes hematopoietic stem cells
In normal zebrafish, blood stem cells in the kidney are protected from sunlight by melanocytes. When this layer is stripped away, stem cell numbers go down. (Image and video below courtesy of the Zon Laboratory and the Howard Hughes Medical Institute.)

Since the late 1970s, biologists have known that blood develops in a specific body location. But they’ve wondered why different creatures house their blood stem cells in different places. In humans and other mammals, they’re in the bone. In fish, they’re in the kidney. Why?

Strange as it seems, the two stem cell “niches” share something in common, say researchers led by Leonard Zon, MD, of Boston Children’s Stem Cell Program, the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the Harvard Stem Cell Institute. Both protect blood stem cells from sunlight’s harmful ultraviolet rays. The findings, published today in Nature, may contain lessons for improving blood stem cell transplants for cancer, blood disorders and other conditions.

First author Friedrich Kapp, MD, a postdoctoral fellow in Zon’s lab, stumbled on this insight accidentally. Looking at zebrafish under the microscope, he noticed that a layer of pigment cells, melanocytes, hovered over the blood stem cell niche in the kidney, but only on the side facing the sun — kind of like an umbrella.

Curious, Kapp mutated zebrafish so that they lacked melanocytes, then exposed them to UV radiation. He found that the number of blood stem cells was decreased. The same was true when he flipped normal zebrafish over and applied UV radiation. The melanocyte “umbrella” was providing a physical shield. The team found similar melanocyte coverings in a variety of other fish.

Seeking better protection

But as animals moved to land and sustained more direct sun exposure, melanocytes apparently weren’t enough to protect their blood stem cells. The researchers studied a type of poison dart frog, looking at different developmental stages. They found that when the tadpoles grew legs, preparing to move to land, the blood stem cells moved from the melanocyte-covered kidney to the bone marrow.

“We now have evidence that sunlight is an evolutionary driver of the blood stem cell niche,” says Zon, who is also a hematologist/oncologist and a Howard Hughes Medical Institute (HHMI) investigator. “Once we understand the niche better, we can make blood stem cell transplants much safer.”

Zon and colleagues will now seek to define the biological signaling pathways that govern the interactions between melanocytes and blood stem cells. What they learn may help the transplanted cells find a safer home in the body.

Kapp, now at the Children’s Hospital in Freiburg, Germany, provides his perspective in this “Behind the Paper” piece in Nature‘s Ecology and Evolution Community. Read more in these press releases from HHMI and the HSCRB. For a full list of co-authors and funders, see the paper.