Mother's stem cells likely key to treating genetic disease before birth

UCSF researchers have tackled a decade-long scientific conundrum, and their discovery is expected to lead to significant advances in using stem cells to treat genetic diseases before birth. Through a series of mouse model experiments, the research team determined that a mother's immune response prevents a fetus from accepting transplanted blood stem cells, and yet this response can be overcome simply by transplanting cells harvested from the mother herself.

"This research is really exciting because it offers us a straightforward, elegant solution that makes fetal stem cell transplantation a reachable goal," said senior author Tippi MacKenzie, MD, an assistant professor of pediatric surgery at UCSF and fetal surgeon at UCSF Benioff Children's Hospital. "We now, for the first time, have a viable strategy for treating congenital stem cell disorders before birth."

Scientists have long viewed in utero blood stem cell transplantation as a promising treatment strategy for many genetic diseases diagnosed as early as the first trimester of pregnancy, including sickle cell disease and certain immune disorders. Fetal stem cell transplantation involves taking healthy cells from the bone marrow of a donor and transplanting them into the fetus through ultrasound-guided injections. When successful, the implanted cells, or graft, replenish the patient's supply of healthy blood-forming cells.

In theory, the developing fetus with an immature immune system should be a prime target for successful transplantation, since the risk of graft rejection is low and the need for long-term immunosuppressive therapy may be avoided. However, most previous attempts to transplant blood stem cells into a human fetus have been unsuccessful, prompting some researchers to lose interest in this promising field, according to MacKenzie, who also is an investigator with the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Findings from the study will appear online January 18, 2011, in the Journal of Clinical Investigation, available at www.jci.org. They also will be published in the journal's February 2011 issue.

"The fact that fetal stem cell transplantation has not been very successful has been puzzling, especially given the widely accepted dogma that the immature fetal immune system can adapt to tolerate foreign substances," said co-senior author Qizhi Tang, PhD, an assistant professor of transplant surgery and director of the UCSF Transplantation Research Lab. "The surprising finding in our study is that the mother's immune system is to blame."

In the study's first phase, researchers examined the cellular content of fetal mouse blood and found a large proportion of maternal blood cells in the fetus. Their analyses indicated that up to 10 percent of the fetus' blood cells came from the mother – a significantly larger percentage of maternal cells than what is found anywhere else in the fetus.