UW-Madison School of Medicine and Public Health: New strategy shows potential in expanding blood stem cells

Contact: Ian Clark
(608) 890-5641
iclark@uwhealth.org

MADISON, Wis. — Cord blood, the blood from a human umbilical cord that contains hematopoietic stem and progenitor cells (blood stem cells and their offshoots), is used to treat an ever-widening range of diseases. The promise and scarcity of finding compatible cord blood transplants for patients in need had University of Wisconsin-Madison scientists searching for ways to expand these valuable cells in the lab.

The Wisconsin Alumni Research Foundation recently secured a provisional patent to protect a new strategy to increase the number of blood stem cells.

According to a new study published early online in Stem Cell Reports, Emery Bresnick, a professor of cell and regenerative biology and the director of the UW-Madison Blood Research Program at the UW School of Medicine and Public Health, has identified a genetic circuit that inhibits blood stem cell production. But in studying the circuit, he’s also identified a compound that can shut down the circuit’s negative feedback loop and promote blood stem cell and progenitor cell production.

If the technology can be applied to cord blood and transferred to the clinical setting, it could one day enable a hospital-based procedure to take a cord-blood sample and multiply its valuable stem and progenitor cells before infusion.

Cord blood can be collected and stored at cord-blood bank facilities until needed. Most cord-blood transplants are coordinated through the National Marrow Donor Program. Once matched, the blood is prepared and delivered through an IV to its recipient. The blood-forming cells then circulate through the body and settle in the bone marrow.

More than 50,000 stem cell transplants occur annually, 2,000 of which are cord blood transplants. Roughly 70 percent of patients in need of a transplant do not have a suitable donor in their family. Unrelated-donor registries currently offer a one in 500,000 chance of finding a match. Patients seeking bone-marrow transplant must match all six HLA types with a donor for a successful match; cord blood matching requires only matching four of the 6 HLAs between donor and patient.

Cord blood has been used to treat many different blood disorders, immunodeficiencies, cancers and other disorders. And while delivery is deceptively simple, the several months after a transplant are critical to the patient’s recovery as physicians monitor the patient’s health and fight infections. But while it’s becoming more common for adult patients to receive multiple cords to help ensure enough stem cells are transfused, the use of multiple cords may be associated with increased graft-versus-host disease, where the newly introduced cells treat the host as foreign. Thus, effective strategies to increase the number of stem cells from a single cord will have multiple benefits.

In a jump from basic research to potential clinical applications, the Bresnick lab has long been studying a gene that controls many different blood-producing functions. During their study of Gata2 (Gata2 the gene, and GATA-2 the protein produced by the gene), Cell and Molecular Biology graduate student Xin Gao and undergraduate researcher Sophie Wu, in collaboration with other members of the Bresnick group, uncovered GATA-2-regulated genes that mediate the generation, survival and function of blood stem cells and progenitors. Unexpectedly, they also discovered that GATA-2 proteins activate a gene that suppresses blood stem and progenitor cell production by turning Gata2 off.

The lab generally thought that every gene GATA-2 proteins turn on would support the genetic machinery that encourages the creation and function of blood stem and progenitor cells, but they discovered a gene that, when reacting with the GATA-2 protein, attempts to turn the Gata2 gene off.

“This was a case where it created a negative feedback,” said Bresnick. “In principle, this mechanism can be disrupted to stimulate the function and production of blood stem and progenitor cells, which is very exciting.”

This discovery was several years in the making. The Bresnick lab wanted to explore the most common target for Food and Drug Administration-approved drugs: G-protein coupled receptors (GPCRs). This large family of cell membrane receptors senses molecules outside the cell and prompts cellular responses. There are more than 800 GPCRs encoded by the human genome, so the lab went about screening each of them to determine if any are regulated by GATA-2. They winnowed and sifted through the whole lot, hoping to find an opportunity to modulate GATA-2 function by either using an existing small molecule or drug, or possibly develop a new one. What they found was GPR65, a receptor for the small molecule psychosine, which is a naturally occurring molecule in the body.

“Through our experiments, we’ve shown that the antagonist of this GPCR, psychosine, stimulates stem and progenitor cell production just like when we lowered the levels of the receptor genetically,” said Bresnick. “We developed multiple lines of evidence indicating that this pathway controls the generation of stem and progenitor cells.”

The Bresnick group is considering the utility of GPR65 antagonists for use in the clinic to expand the number of hematopoietic stem and progenitor cells in cord blood with hopes of treating malignant and non-malignant disorders.