# Immunomodulatory effects of primed amniotic fluid-derived mesenchymal stem/stromal cells with IFN-γ from unexplained recurrent miscarriage sources

## TL;DR

This study explores how stem cells from amniotic fluid respond to immune signals in cases of unexplained recurrent miscarriage.

## Contribution

It reveals that stem cells from miscarriage cases show impaired immune response to IFN-γ, potentially explaining RPL.

## Key findings

- hAF-MSCs from RPL cases showed altered IFN-γ-induced immunomodulatory gene expression.
- RPL-derived hAF-MSCs had reduced capacity to induce Treg cells and modulate macrophage polarization.
- These findings suggest impaired IFN-γ responsiveness in hAF-MSCs may contribute to unexplained RPL.

## Abstract

The immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) are strongly influenced by IFN-γ priming and may vary depending on their tissue of origin. This study investigates whether the immunoregulatory responses of human amniotic fluid-derived MSCs (hAF-MSCs) to IFN-γ are altered when derived from individuals with unexplained recurrent pregnancy loss (RPL). We analyzed 10 well-characterized hAF-MSC clones, equally divided into non-RPL and RPL groups, to assess IFN-γ-induced expression of immunomodulatory genes. Additionally, we evaluated the paracrine effects of MSC-conditioned medium on T regulatory (Treg) cell induction and macrophage polarization. Significant differences were observed between the two groups in the expression of immunomodulatory markers following IFN-γ priming, as well as in their capacity to induce Treg cells and modulate M1/M2 macrophage polarization. These findings support the hypothesis that dysregulated immune pathways contribute to unexplained RPL by revealing impaired IFN-γ responsiveness in hAF-MSCs from fetuses derived from couples with the history of RPL.

The online version contains supplementary material available at 10.1038/s41598-025-01799-1.