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Fetal blood stem cells need surprise helper: bile


A discovery by Lund University scientists could advance transplants.

Why do fetuses have bile? This compound usually goes from the gall bladder to the intestines to help digest fats. “It seems strange,” says Assistant Professor Kenichi Miharada at Lund University Division of Molecular Medicine and Gene Therapy, “because fetuses don’t eat food, so they don’t need bile for digestion.” In a recent Cell Stem Cell paper, Miharada’s group solved the riddle: they found that in mice, bile from mothers helps fetuses produce blood stem cells.

Blood stem cells have the potential to become all other types of blood cells. That’s why they are used in transplants, for example to replace the cancerous cells in people with leukemia. However, says Miharada, “in culture, blood stem cells lose that potential. My group is trying to solve this problem.” From earlier work, the researchers knew that when blood stem cells are cultured, they are stressed by the burden of producing large amounts of protein. The scientists also knew that treating cultured cells with bile helps prevent newly produced proteins from tangling.

In their recent study, Miharada says they focused on the rapid expansion of blood stem cells in the fetal liver. “The cells grow efficiently there,” he says. “We wondered how they did that without the problem of abnormal and unfolded proteins. We thought bile might reduce the stress.” In fact, the scientists found that in mice, maternal bile goes through the placenta to the fetus to assist with protein folding during blood cell development. Miharada says that clinical researchers he talked with confirmed that human fetuses also have bile, but until now, they didn’t know why.

Japanese partnerships to improve Swedish transplants

The Miharada group is now doing studies in mice to determine the effects of low bile in the fetus. They hypothesize that this condition could harm blood stem cells during early development, increasing the risk of leukemia later in adulthood. Other studies from the Miharada lab might have an impact even sooner on human health.

The researchers are studying if bile can improve the culturing of human blood stem cells. Although bile acids can be harmful, the form of bile in the fetal mouse liver is nontoxic. It might help to safely grow umbilical cord stem cells for transplants. These cells have great potential but are so few that they are usually cultured in vitro before use. Miharada notes that in Japan, compared to Sweden, transplants using cord stem cells instead of adult bone marrow stem cells are much more common. The Miharada group works with partners at Nihon University and Junshin Clinic Bile Acid Institute in Tokyo. Among their projects is testing if adding bile to cultures helps expand the population of transplant-quality cord stem cells. This could increase the availability of these cells for transplants in Scandinavia.


Sigurdsson V, Takei H, Soboleva S, Radulovic V, Galeev R, Siva K, Leeb-Lundberg LMF, Iida T, Nittono H, Miharada K. Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver. Cell Stem Cell, 2016; 18:522-32.


Photo showing left to right: V Sigurdsson, K Miharada, V Radulovic, S Soboleva, M van der Garde. Photo: Kataria Branzen