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

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

http://www.eurekalert.org/bysubject/medicine.php

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.

" We had previously known that a minute amount of cells travel from the mother

into a developing fetus and that this is an important tolerance mechanism in all

healthy pregnancies, " MacKenzie said. " However, the unexpectedly large

proportion of maternal blood cells in the fetus made us think that perhaps it

was the maternal, rather than the fetal, immune response that poses the real

barrier to effective stem cell transplantation. "

To further investigate this hypothesis, the team transplanted fetal mice with

blood stem cells from a second strain of mice that were not matched to the fetus

or the mother. Following transplantation, the researchers observed an influx of

T cells – the major driving force behind an immune response – from the mother

into the fetus, which subsequently led to rejection of the transplanted graft.

However, if the researchers removed T cells only from the mother before carrying

out the transplant, nearly 100 percent of the injected fetuses engrafted, or

accepted the transplanted cells, indicating that maternal T cells play the

critical role in triggering transplant rejection. Finally, the researchers

transplanted fetal mice with blood stem cells matched to the mother, which, as

expected, resulted in a very high success rate.

" As long as the transplanted stem cells are matched to the mother, it does not

seem to matter if they are matched to the fetus, " said first author Amar

Nijagal, MD, a postdoctoral research fellow and surgery resident at UCSF.

" Transplanting stem cells harvested from the mother makes sense because the

mother and her developing fetus are prewired to tolerate each other. "

As next steps, researchers will need to confirm that the findings are consistent

in humans and also will investigate how exactly maternal T cells cause a graft

rejection.

" Now that we know a fetus can become tolerant to a foreign stem cell source, we

can really think big and consider looking at how other types of stem cells might

be used to treat everything from neurological disorders to muscular disorders

before birth, " MacKenzie added.

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Additional authors include Marta Wegorzewska, Jarvis, and Tom Le, all with

the Eli and Edythe Broad Center of Regeneration Medicine and the UCSF Department

of Surgery.

The study was funded through support from the Irene Perstein Award, UCSF Sandler

Funds, the American Pediatric Surgical Association, the National Institutes of

Health, the California Institute for Regenerative Medicine, the National Science

Foundation, and the Joslin Diabetes and Endocrinology Research Center.

UCSF Benioff Children's Hospital creates an environment where children and their

families find compassionate care at the forefront of scientific discovery, with

more than 150 experts in 50 medical specialties serving patients throughout

Northern California and beyond. The hospital admits about 5,000 children each

year, including 2,000 babies born in the hospital. For more information, visit

www.ucsfbenioffchildrens.org.

UCSF is a leading university dedicated to promoting health worldwide through

advanced biomedical research, graduate-level education in the life sciences and

health professions, and excellence in patient care. More information is

available at www.ucsf.edu.