Hyaluronic acid-CD44 signaling from decidual stromal cells orchestrates dNK1 differentiation and immune tolerance in early pregnancy.

Spontaneous abortion (SA) is closely associated with immune homeostasis of decidual natural killer (dNK) cells at the maternal-fetal interface, yet how decidual stromal cells (DSCs) educate NK cells remains incompletely understood. Here, we showed that DSC-derived hyaluronic acid (HA) shapes NK cell residency and cytotoxicity in early pregnancy. Reanalysis of single-cell RNA sequencing data and functional assays identified DSCs as the major source of HAS2-dependent HA. We assessed dNK phenotypes and functions in SA versus normal pregnancies, and tested HA -CD44 effects using high-molecular-weight HA (HMW-HA) stimulation, HAS2 knockdown in DSCs, and CD44 blockade, with partial rescue by exogenous HMW-HA. Canonical Wnt activation and FOSL2 upregulation were further evaluated by western blotting to examine downstream signaling. Our findings revealed a reduced proportion of dNK cells, impaired adhesion molecule expression, and increased cytotoxicity in SA compared with normal pregnancies. HMW-HA from DSCs, via engagement of CD44 on NK cells, promoted the phenotypic transition of peripheral NK cells into CD49a+ tissue-resident dNK-like cells, increased adhesion, and shifted cytokine production toward an immune-tolerant profile. HAS2 knockdown in DSCs or CD44 blockade reduced CD49a expression, expanded highly cytotoxic CD44high subset, and disrupted the balance among dNK1/dNK2/dNK3-like subsets, effects that were partially rescued by exogenous HMW-HA. Mechanistically, HA/CD44 signaling activated canonical Wnt pathways and upregulated the dNK1-associated transcription factor FOSL2, driving differentiation toward a low-cytotoxic dNK1-like phenotype. These findings define a DSC-centered HA/HAS2 -CD44 -Wnt -FOSL2 axis that remodels NK cells and supports maternal-fetal immune tolerance, providing potential targets for preventing SA and related pregnancy complications.