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Overcoming poor fetal nutrition?
Natural killer (NK) cells are among the most abundant immune cells in the uterus during the first trimester of pregnancy. Their numbers decline substantially after the placenta forms. A study published December 19th in the journal Cell: Immunity shows that this transient cell population helps optimize mom's ability to nourish her fetus at its earliest stages of development. Researchers identified a specific set of uterine natural killer cells that secrete growth-promoting factors both in humans and mice. They then demonstrated how transferring these cells can reverse poor fetal growth in pregnant mice.
"These findings not only reveal new properties of natural killer cells during early pregnancy, but also point to approaches for therapeutic administration of natural killer cells in order to reverse restricted nourishment within the uterine microenvironment. The study will have major implications for our approach to adoptive cell therapy strategies for the generation of not only natural killer cells against pathogens and tumors, but also natural killer cells supporting body development and tissue engineering."
Acting as our bodies' frontline defense system, NK cells guard against tumors and launch attacks against infections. For decades, NK cells in the uterus have been studied as an example of how specialized immune cells are endowed with unique functions developed during the evolution of mammalian pregnancy. A primary example of their function is that uterine NK cells promote the growth of blood vessels in the placenta. They also have a positive impact on immune balance, fetal birth weight, as well as fetal growth. But until now, which subset of NK cells in the uterus were responsible for promoting fetal growth, or whether these cells helped optimize fetal nourishment in early developmental stages wasn't clear.
In this new study, Wei and co-senior author Zhigang Tian, also of the University of Science and Technology, China, have discovered which specific subset of NK cells in the human uterine lining secrete growth-promoting factors called pleiotrophin and osteoglycin. Both groups of NK cells were found to be smaller (42%) in volume in the uterine lining of patients suffering recurrent spontaneous abortion, as compared to healthy patients (81%) with full term pregnancies. This observation suggests insufficient secretion of growth-promoting factors by these specific subsets of NK cells may be responsible for restricted fetal development.
Additional studies in mice show that a deficiency in pleiotrophin and osteoglycin results in severe fetal growth restriction and defective development of the fetal skeletal system. Remarkably, the transfer of uterine-like NK cells reversed fetal growth impairments in these mice.
It remains unclear how growth-promoting factors affect fetal development:
(A) directly through the maternal-fetal barrier, or
(B) indirectly by promoting placental and blood vessel growth.
Clinically, NK cells-based immunotherapy has been widely used to treat cancer. Now, for the purpose of promoting fetal growth in humans, it may be possible to transfer NK cells via intravenous infusion, or by vaginal suppositories to mothers, and avoid the need for invasive procedures. Moreover, uterus-like NK cells are a much safer alternative than pluripotent stem cells as they are less likely to induce tumor formation.
"Additional studies are needed to explore the most suitable protocols to induce uterus-like NK cells that secrete growth-promoting factors in a human system, and to improve the feasibility of applying these uterus-like NK cells to patients. This study provides an avenue for treating fetal growth restriction, recurrent spontaneous abortion with unknown reasons, and age-related fetal loss by improving the uterus microenvironment."
Zhigang Tian PhD, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, and Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, China; and co-senior author.
• Uterine CD49a+Eomes+ trNK cell subset secretes GPFs including pleiotrophin and osteoglycin
• A decrease in the GPF-secreting trNK cell subset impairs fetal development
• Adoptive transfer of uterine-like trNK cells can reverse impaired fetal growth
Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.
Authors: Binqing Fu, Yonggang Zhou, Xiang Ni, Xianhong Tong, Xiuxiu Xu, Zhongjun Dong, Rui Sun, Zhigang Tian, Haiming Wei, Haiming Wei Jr.
This work was supported by the Natural Science Foundation of China.
Immunity (@ImmunityCP), published by Cell Press, is a monthly journal that reports the most important advances in immunology research. Topics include: immune cell development and senescence, signal transduction, gene regulation, innate and adaptive immunity, autoimmunity, infectious disease, allergy and asthma, transplantation, and tumor immunology. Visit: http://www.cell.com/immunity. To receive Cell Press media alerts, contact firstname.lastname@example.org.
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An artistic rendering of how NK cells promote fetal growth in early pregnancy.
Image credit: Binqing Fu.