Protein Is Vital to Successful 'Homing' of Stem Cells, Researchers Discover

CINCINNATI—Researchers at the University of Cincinnati (UC) Hoxworth Blood Center and Cincinnati Children’s Hospital Medical Center have discovered that a protein called Klf5 is required for successful "homing” of stem cells in the bone marrow during stem cell transplantation.

Stem cells lacking Klf5, the researchers found, failed to engraft after transplantation, thereby reducing the efficiency of bone marrow transplants. Such transplants are used during the treatment of blood cancer and genetic blood diseases to restore blood cell formation in bone marrow that has been damaged by high-dose chemotherapy or radiation therapy.

The findings are being published today (April 3, 2013), in Nature Communications, an online multidisciplinary scientific journal.  

"Stem cell transplantation is a technique used in millions of patients worldwide,” says Jose Cancelas, MD, PhD, one of the study authors and a professor of pediatrics at UC and deputy director of Hoxworth Blood Center. "Unfortunately, the outcome of this procedure may be jeopardized in a fraction of patients due to reduced engraftment within the bone marrow.”

During high-dose radiation therapy treatment, given to kill advanced cancer, normal stem cells found in bone marrow are also destroyed. Without a bone marrow transplant, new blood cells cannot be produced and the patient will die. 

When bone marrow or adult stem cells are taken from a matching donor and injected into the patient after radiation or chemotherapy, the cells move through the recipient’s bloodstream and settle in the same type of tissue they inhabited in the donor. This process is called "homing” and is crucial to the success of the transplant.

Using transgenic mice, Cancelas’ group, in collaboration with Lee Grimes, PhD, an associate professor of pediatrics and pathology at UC based at Cincinnati Children’s, and Jeffrey Whitsett, MD, a UC professor of pediatrics based at Cincinnati Children’s, demonstrated that Klf5, a member of the Kruppel-like factor subfamily of zinc finger proteins that function in DNA binding, is required for the adhesion, homing and engraftment of hematopoietic stem cells (stem cells that can take on the role of any cell in the body). When Klf5 was deleted in the mice, their ability to engraft in bone marrow was impaired.

"Although Klf5 is not essential for hematopoietic stem cell self-renewal, it is an essential factor for controlling engraftment, homing and retention in the bone marrow,” says Cancelas.

"The specific roles of Klf5 in postnatal stem cell activity remain to be identified,” study authors state, suggesting a target for future research.

Additional authors of the study were E. Taniguchi Ishikawa, PhD, and Kyung-Hee Chang, PhD, Hoxworth Blood Center and Cincinnati Children’s; Susan Dunn, Hoxworth Blood Center; and Ashley Ficker, Malav Madhu, Ramesh Nayak, PhD, Andre Olsson, PhD, and  Amitava Sengupta, PhD, Cincinnati Children’s.

Funding was provided by the U.S. Department of Defense, the Heimlich Institute of Cincinnati, Hoxworth Blood Center and Cincinnati Children’s.