Bioreactor yields marrow-like cell mixture.

In the soft, gelatinous cores of breast, rib, arm, and leg bones toil the body's blood-producing factories. There, primitive stem cells divide, mature, and transform into a varied cast of cells that can clot, carry oxygen, and defend against foreign invaders. Researchers recently isolated the mysterious human stem cell (SN: 11/9/91, p. 292), and they now hope to harness its blood-cell-building power.

A new report suggests that the secret of stem cell differentiation lies in the shape of its surroundings. Using a three-dimensional "bioreactor" for culturing bone marrow tissue, J.H. David Wu and his colleagues at the University of Rochester (N.Y.) have shown that they can produce almost all of the stages and subtypes of human blood cells - a significant improvement over the commonly used two-dimensional flask culture system, which produces only two cell types.

"This kind of culture is a better model of what goes on inside the body," says Wu, who described his team's work this week at a meeting of the American Chemical Society in Denver. Wu hypothesizes that bone marrow contains a rich variety of biochemical niches that coax stem cells to develop into diverse cell types. The bioreactor's three-dimensional scaffold creates a similar environment, making possible extensive cell-to-cell contact and exposure to growth factors.

Researchers hope someday to grow substantial quantities of bone marrow in laboratory bioreactors in order to boost the availability of the tissue for transplantation into patients with leukemia and other cancers and to reduce the need for donors, who at present must be anesthetized while a quart of marrow is removed by aspiration. Efficient bioreactors could also enable researchers to culture genetically engineered blood cells for transfusion back into patients with hereditary blood diseases.

To make a bioreactor that mimics the porous environment of real bone marrow, Wu's group packed a small plastic shell with several milliliters of spongy material such as animal collagen, a protein abundant in marrow. They inoculated the reactor with cells from whole human bone marrow. An automated "circulatory" system bathed the contents with a flow of nutrients and oxygen and removed the lactic acid and other waste products produced.

The reactor generated nearly all of the cells found in natural marrow, including red blood cells, megakaryocytes (which form platelets), and white blood cells such as lymphocytes, macrophages, and all three types of granulocytes, Wu says. The two-dimensional flask culture system produces only macrophages and one type of granulocyte.

"This is an important and interesting development," comments lan Ponting, a stem ceil biologist at Amgen, Inc., in Thousand Oaks, Calif. Now the race is on to build a commercial bone marrow bioreactor. Bernhard Palsson of the University of Michigan in Ann Arbor predicts that companies investigating such a bioreactor will develop a superior matrix that allows for easy harvesting of the blood cells.

Says Wu, "Our reactor is not very fancy and could have many different designs as long as the three-dimensional design is preserved, which appears to be the key,"