Scientists spot solitary stem cells in living bone marrow

Blood-forming stem cells appear to want to live alone, according to new research by scientists at Japan's University of Tsukuba and the U-M Medical School.

A single glowing blood-forming stem cell is shown with living mouse bone marrow cells. Researchers from the Medical School and University of Tsukuba in Japan have found these stem cells tend to live in isolation. (Photo by Douglas Engel)

Until now, scientists didn't know exactly where to find these extremely rare, elusive adult stem cells—the only cells capable of forming all the different types of blood and immune cells found in mammals. Previous research suggested, and most scientists believed, that hematopoietic stem cells were clustered together somewhere in bone marrow.

But a new study published last week in the Proceedings of the National Academy of Sciences online Early Edition provides compelling visual evidence that hematopoietic, or blood-forming, stem cells prefer a solitary life.

"We took time-lapse movies of sections from mouse leg bone as seen under a fluorescent microscope," says Douglas Engel, chair and professor of cell and developmental biology at the Medical School, who is the corresponding author for the study. "They clearly show individual, isolated hematopoietic stem cells at the edge of the bone marrow."

According to Engel, the discovery will make it possible to study hematopoietic stem cells undisturbed and in their natural environment. That's important, he says, because when stem cells are removed from bone marrow, they either die or start differentiating—changing into different types of specialized blood cells.

"There's something about the physical location and cellular environment surrounding stem cells in their bone marrow niche that is at least partly responsible for their ability to maintain a primitive, pluripotent state," Engel says. "Now that we can visualize them in vivo, we are in a better position to find out how they do it."

According to Engel, scientists currently identify a hematopoietic stem cell by looking for a unique pattern of protein markers found on the cell's surface. The process is complicated and the flow cytometry equipment used to sort the cells is expensive. Plus the sorting process removes stem cells from their natural bone marrow environment, which changes their properties in fundamental ways.

To verify that cells identified with their Gata2-GFP marker technique were true hematopoietic stem cells, Suzuki and his colleagues conducted a series of experiments to test the purity of their cell samples against cells selected using conventional hematopoietic stem cell markers.

"We validated our findings using existing techniques, and found that the hematopoietic stem cells identified in this new way have all the known properties of HSCs," Engel says.

Specifically, the researchers found that:

• GFP was seen only in immature hematopoietic progenitors that lacked the surface protein markers seen in more mature types of blood cells;

• Only those cells with GFP activity had the ability to reconstitute the bone marrow of mice whose hematopoietic stem cells were destroyed by high doses of radiation;

• HSCs with green fluorescent protein were immobile and found in contact with osteoblasts, or bone-forming cells, at the edge of mouse bone marrow.