Blood-forming stem cells fail to repair heart muscle

Stanford Report, March 31, 2004

Blood-forming stem cells fail to repair heart muscle
Study casts doubt on one avenue of cardiac research

By AMY ADAMS

A new study adds a twist to the ongoing debate over using blood-forming stem cells to repair heart muscle. In the March 21 online issue of Nature, researchers at the School of Medicine reported that the cells are unable to replace heart muscle after a heart attack, which refutes earlier findings.

During the past three years, several groups had reported that stem cells found in bone marrow could lodge in the heart and repair muscle damaged by a heart attack. These stem cells normally reside in the bone marrow, where they constantly replenish red blood cells and immune cells.

If the earlier findings were correct and the blood-forming stem cells switched their fates, that could reveal an exciting new path for treating heart attack patients.

"We started out attempting to validate and extend those findings," said Leora Balsam, MD, a research fellow working with Robert Robbins, MD, associate professor of cardiothoracic surgery.

Instead of supporting previous findings, however, her experiments contradicted them. She found that in mice, blood-forming stem cells lodge in damaged hearts but retain the form of blood cells rather than transforming into muscle cells. A paper by another research group in the same issue of Nature supports Balsam's findings using slightly different methods.

The question now is why some studies have found that blood-forming stem cells can repair the heart while others show that those adult stem cells retain their blood-forming fate. The question is particularly timely given that human trials are already under way based on the strength of earlier findings refuted by the new research.

"If we are delivering bone marrow to patients with the expectation that it will regenerate the heart, that may not be realistic," Balsam said.

One difference between Balsam's study and previous experiments is the type of bone marrow cells she used. Amy Wagers, PhD, a postdoctoral scholar in the lab of Irving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology, took whole bone marrow from mice then isolated several purified groups of cells, including a highly purified subset of stem cells that can go on to form all blood cell types. Previous experiments had only used less purified cells.

Balsam injected those cells directly into the heart muscle of 23 mice in which she had induced a heart attack. The injected cells produced a green protein that is easily visible under a microscope. She then examined the heart muscles of those mice 10 days and 30 days after the injection to search for signs of transplanted blood-forming stem cells.

At 10 days she saw clusters of green cells, but none of them made proteins typical of heart muscle. However, the green cells did produce proteins commonly made by blood cells. By 30 days, very few green cells remained in the heart, and those that did still produced blood proteins rather than heart muscle proteins.

Balsam found that 30 days after injecting the blood-forming stem cells, the mice died at the same rate as those in another group that received only water after their induced heart attacks. Even though the transplanted stem cells didn't help the mice survive, the stem cell-injected group did have slight improvements in how well their hearts pumped blood.

Robbins, who is lead author of the study, said even with these results, adult stem cells may offer some potential for treating damaged hearts. "Maybe these cells don't need to differentiate," he said.

Robbins said the transplanted blood-forming cells may recruit new blood vessels to the damaged tissues. These new blood vessels may keep heart muscle cells alive that would otherwise have died, thus indirectly rescuing the heart. By genetically engineering those cells to make additional factors to recruit blood vessels, they may become part of a successful therapy, Robbins said.

Researchers are also examining embryonic stem cells and immature skeletal muscle cells as possible candidates for repairing heart muscle. Robbins and other members of his lab are looking into these alternative ways of repairing heart muscle.

"We're all interested in finding ways of regenerating the heart," Balsam said. "I think what this study points out is that it's not easy."

Researchers track stem cells in the act of morphing (11/20/02)

Sen. Specter blasts government stand on stem cells (2/25/04)