What question did this study set out to answer?

The research aims to understand how decidual stromal cells influence NK cell differentiation and immune tolerance during early pregnancy.

March 29, 2026Frontiers in Immunology1 citationsOpen Access

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

DWDi WangZhongyuan University of Technology JZJunwei ZhuNingbo University QWQingzhi WangSuzhou Municipal Hospital

Key Points

The research aims to understand how decidual stromal cells influence NK cell differentiation and immune tolerance during early pregnancy.
Reanalyzed single-cell RNA sequencing data for gene expression patterns.
Conducted functional assays to assess effects of hyaluronic acid and CD44 signaling.
Examined dNK cell phenotypes in spontaneous abortion versus normal pregnancies.
Used HAS2 knockdown in DSCs and CD44 blockade to analyze impacts on NK cells.
Evaluated Wnt signaling and FOSL2 expression through western blotting.
Spontaneous abortion was linked to fewer dNK cells, increased cytotoxicity, and altered adhesion molecule expression.
HMW-HA from DSCs engaged CD44, promoting transition to dNK-like cells and enhancing immune tolerance.
HAS2 knockdown led to reduced dNK1-like cells and disrupted the balance of dNK subsets.
HA/CD44 signaling activated Wnt pathways and upregulated FOSL2, fostering differentiation towards a low-cytotoxic phenotype.

Abstract

Introduction 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. Methods 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. Results 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 CD44 high 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. Discussion 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.

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