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Problem: Decidual natural killer (dNK) cells play key roles in maternal-fetal immune regulation, trophoblast invasion, and vascular remodeling, and most dNK cell populations are CD56 bright CD16 − NK cells. However, the enrichment and redistribution of dNK cells in the local decidua have not been clarified yet. Method of study:A total of 45 women with normal pregnancies and 8 unexplained recurrent spontaneous abortion (RSA) patients were included. We isolated primary human dNK (n = 53) and peripheral blood NK (pNK) cells (n = 5) from specimen and analyzed CD56, CD82, and CD29 by flow cytometry (FCM). We assessed their adhesion ability by cell counts of NK cells adhered to decidual stromal cells (DSCs) in a co-culture system. Results:We found that RSA patients had more CD56 dim dNK cells with lower CD82 and higher CD29 than women with normal pregnancies. There were negative correlations of CD82 to CD29 on CD56 dim and CD56 + dNK cells. In normal pregnancies, dNK cells had lower CD82 and higher CD29 expression with a stronger adhesion ability than pNK cells. Blocking CD82 on dNK cells increased the adhesive ability and CD29 expression, while blocking CD29 decreased the adhesive ability. Co-culturing dNK cells with trophoblast cells decreased CD82 expression and increased the adhesive ability of dNK cells and the percentage of CD56 bright NK cells, while blocking trophoblast-derived CXCL12 increased CD82 expression, decreased CD29 expression, and impaired the adhesive ability of NK cells. Conclusion: Trophoblast cells enhance the adhesive ability of NK cells to DSCs viathe CXCL12/CD82/CD29 signaling pathway and contribute to CD56 bright NK cell enrichment in the uterus. K E Y W O R D S abortion, adhesion, CD29, CD82, CXC12, decidua, NK, trophoblasts How to cite this article: Lu H, Jin L-P, Huang H-L, et al. Trophoblast-derived CXCL12 promotes CD56 bright CD82 − CD29 + NK cell enrichment in the decidua.Am J Reprod Immunol. 2020;83:e13203.

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Study question How does the androgen receptor splice variant (ARSV) contribute to insulin resistance in polycystic ovary syndrome (PCOS) patients? Summary answer ARSV inhibited the intracellular signaling pathway of insulin, resulting in decreased glucose transporter type 4 (GLUT4) translocation, impaired cellular glucose uptake, and insulin resistance. What is known already PCOS is the most common endocrine disorder in women of reproductive age and characterized by hyperandrogenism, ovulation dysfunction, and ovarian polycystic changes. In addition, a significant proportion of PCOS patients will experience insulin resistance. Our previous study identified an ARSV in granulosa cells from PCOS patients, which may be associated with higher insulin levels in follicular fluid. Study design, size, duration / Participants/materials, setting, methods Glucose metabolism of a mouse model presenting ARSV by CRISPR-Cas9 was measured by glucose tolerance test and insulin tolerance test. Body composition was measured by a nuclear magnetic resonance system. KGN cell lines stably overexpressing wild type androgen receptor (AR group) or ARSV (ARSV group) were successfully constructed by lentivirus infection. The process of glucose uptake by GLUT4, and the expression of target genes in the glucose uptake pathway were detected in cells. Main results and the role of chance The mice expressing ARSV had higher body weight and body fat content than the wild type mice, while the muscle content was equivalent.ARSV mice displayed diabetes with impaired glucose tolerance and insulin tolerance at 48 week-age. The levels of fasting glucose and insulin levels were significantly higher in ARSV mice. The basal and insulin-stimulated glucose uptake capacity were also found impaired in ARSV group. Immunofluorescence demonstrated that under insulin stimulation, GLUT4 protein was less expressed in the membrane and more expressed in the cytoplasm in ARSV group. Similar results were obtained by detecting the expression of GLUT4 protein after separating the cell membrane and cytoplasmic proteins. Further detection of the upstream signaling molecules of GLUT4 revealed that the phosphorylation levels of insulin receptor substrate 1 (IRS1) at Ser1101 were slightly increased in ARSV group, after stimulation with insulin and DHT. Besides, the phosphorylation levels of protein kinase B (AKT) were also found significantly decreased at Thr308 and slightly decreased at Ser473 in ARSV group. ARSV inhibited the intracellular signaling pathway of insulin by altering the phosphorylation level of IRS1/AKT signaling, resulting in decreased GLUT4 translocation, impaired cellular glucose uptake, and insulin resistance. Limitations, reasons for caution In this study, we failed to obtain clinical samples of PCOS to prospectively verify the association between ARSV and glucose uptake, insulin resistance, and subsequent onset diabetes. Wider implications of the findings This transgenic animal model can simulate the reproductive and metabolic phenotypes of PCOS patients, providing a model for future PCOS research. PCOS patients with ARSV should delay the onset of insulin resistance through lifestyle intervention, exercise, and drug therapy as early as possible. Trial registration number NA

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