Stem Cell Discovery Could Improve Bone Marrow Transplantation

Liver is the surprising source of a growth factor that keeps bone marrow stem cells healthy

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New research from Columbia stem cell scientists has found that a growth factor from the liver keeps hematopoietic stem cells (red) healthy. The research could lead to improvements in bone marrow transplantation. Image: Lei Ding / Columbia University Irving Medical Center.

New findings about hematopoietic stem cells—which give rise to all blood cells—could lead to improvements in bone marrow transplantation, say scientists at Columbia University Vagelos College of Physicians and Surgeons and the Columbia Stem Cell Initiative.

In bone marrow transplantation—often used to treat blood cancer—healthy bone marrow cells are transferred to a patient to replace diseased cells.

The study, published in the latest issue of Science, uncovered the source of a key growth factor that, in mice, keeps blood-forming hematopoietic stem cells (HSCs) in a healthy state inside bone marrow. Without the growth factor, HSCs cannot maintain themselves or create new blood cells.

The source of the growth factor—the liver—came as a surprise, says the study’s senior author Lei Ding, PhD, assistant professor of rehabilitation & regenerative medicine and of microbiology & immunology. All other known factors needed for HSC maintenance are supplied locally by the bone marrow.

“Our study tells the field that to find the factors that can improve bone marrow transplantation, it needs to broaden the search beyond the bone marrow,” Ding says.

For a bone marrow transplant to be successful, HSCs must embed themselves in the recipient’s bone marrow, where they will reconstitute the patient’s blood cells.

But HSCs are rare and only represent about 1 percent of the cells transferred during the procedure. “Most cells transferred in a bone marrow transplant are mature cells that help the patient for a short period of time,” Ding says. “The HSCs give you the lifelong cure.”

Increasing the number of HSCs infused into the patient could improve transplant success, but scientists have so far been unable to multiply HSCs in the lab. “That’s because we don’t fully understand all the factors necessary to maintain HSCs,” Ding says.

In the study, Ding and his colleagues tried to track down the source of one of these factors, a growth factor called thrombopoietin or TPO. They first looked in the bone marrow, but when the researchers prevented the bone marrow’s production of TPO, there was no effect on HSCs.

That prompted the researchers to look elsewhere. Only when the researchers turned off TPO production in the liver did they see an effect on HSCs: Without TPO from the liver, almost all of the HSCs are lost.

“It was a striking finding, but it makes sense in retrospect,” Ding says. “For an organism to function properly, all organs have to talk to each other.”

“We need more of such insightful study identifying important mechanisms for stem cell transplantation and regenerative medicine approaches,” says Emmanuelle Passegué, PhD, director of the Columbia Stem Cell Initiative.

Ding thinks that the same liver-HSC crosstalk may occur in people—people with liver disease often have HSC problems—and his lab is now looking to confirm that.

References

Lei Ding is an assistant professor of the Columbia Stem Cell Initiative in the Department of Rehabilitation & Regenerative Medicine and Department of Microbiology & Immunology.

The study is titled “Hepatic thrombopoietin is required for bone marrow hematopoietic stem cell maintenance.” Other authors: Matthew Decker, Juliana Leslie, and Qingxue Liu (all from Columbia University Vagelos College of Physicians and Surgeons).

This work was supported by the Rita Allen Foundation and the National Institutes of Health (grants R01HL132074 and F30HL137323).

The authors declare no competing interests.