Illustration of human Fetus in the Womb during pregnancy showing placenta to represent placental health issues
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Research led by the Yale School of Medicine shows the immune protein C-X-C chemokine receptor type 4 (CXCR4) plays an important role in maintaining healthy pregnancy through the placenta and could be a potential target for future therapeutics.

Previous work showed CXCR4 helps move bone marrow cells around the body. It is seen at higher-than-normal levels in the uterus at the start of pregnancy, but the reasons for this were previously unclear.

Natural killer cells and dendritic cells are important for early placental development and for regulating immune tolerance between the mother and the fetus and CXCR4 helps regulate these immune cells.

“Previous findings imply there is an important function for CXCR4 in pregnancy,” said Reshef Tal, assistant professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine and senior author of the study, in a press statement. “We wanted to understand its overall role in pregnancy maintenance and immune function in the decidua.”

Writing in the journal JCI Insight, Tal and colleagues evaluated the function of CXCR4 in genetically engineered mice without functional CXCR4 protein.

Female mice without functional CXCR4 had more miscarriages and smaller litter sizes than those with normal levels of this protein. However, when the researchers isolated the mutation to cells in the uterus alone it did not adversely impact pregnancy in the mice.

“That finding suggested that it’s not the CXCR4 expression within the uterine cells themselves, but rather it’s the CXCR4 expression from outside of the uterus that plays an important role in pregnancy maintenance,” said Tal.

Looking more specifically at placental development in mice with abnormally low levels of CXCR4, the researchers found that fewer natural killer cells clustered in the uterus and those that were there behaved abnormally and released less granzyme B. This appeared to trigger abnormal inflammation levels in the uteruses of these mice.

“Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes,” write the authors.

“Importantly, adoptive bone marrow transfer of wild type CXCR4+ bone marrow cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development.”

These results are promising, but more research needs to be completed to investigate if women with pregnancy disorders have abnormal levels of CXCR4 and whether therapeutics targeting this protein could help promote healthy pregnancies in the future.

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