Impaired Midkine/Treg Signaling Contributes to Pathogenesis of Preeclampsia

BACKGROUND: Early-onset preeclampsia is characterized by maternal-fetal immune dysregulation and trophoblast dysfunction, commonly presenting with a reduction in regulatory T cells (Tregs) and impaired trophoblast invasion. However, the precise role of aberrant Treg-trophoblast communication in early-onset preeclampsia progression remains unclear. METHODS: A preeclampsia-like syndrome mouse model was established by administration of the nitric oxide inhibitor, NG-nitroarginine methyl ester hydrochloride. Mouse natural Tregs were adoptively transferred into the NG-nitroarginine methyl ester hydrochloride model via tail vein injection. Confirmatory experiments were conducted using an additional preeclampsia-like syndrome model generated by the administration of iMDK (MDK [midkine] and PI3K/Akt [the phosphatidylinositol 3-kinase/protein kinase B] inhibitor). An in vitro coculture model was established using a trophoblast cell line and human Tregs isolated from both umbilical cord/placental blood and maternal peripheral blood. RESULTS: Placentas from patients with early-onset preeclampsia had reduced numbers of Tregs compared with healthy controls. Adoptive Treg transfer activated the TβR1 (transforming growth factor β type I receptor)/Smad3 (Sma- and Mad-related protein 3) signaling pathway in trophoblasts, thereby enhancing their invasive and proliferative capacities and ultimately mitigating preeclampsia-like syndrome. Moreover, maternal peripheral blood MDK levels exhibited a significant inverse correlation with disease severity. MDK upregulates LAP (latency-associated peptide) expression on Tregs and acts synergistically with adoptive Treg transfer, resulting in a more pronounced therapeutic effect than Treg transfer alone. CONCLUSIONS: This study demonstrates that restoring Tregs ameliorates preeclampsia-like syndrome by enhancing trophoblast function. We further identify MDK as a key mediator enhancing this therapy, which upregulates LAP expression on Tregs and synergistically improves its overall efficacy against early-onset preeclampsia.