# Mesenchymal Stem Cells Restore Endometrial Integrity and Sustain Pregnancy via CCR7‐ERK/JNK Signaling Modulation

## TL;DR

Mesenchymal stem cells help repair the endometrium and support pregnancy by modulating immune cells and signaling pathways in a rat model of recurrent pregnancy loss.

## Contribution

The study identifies the CCR7-ERK/JNK signaling axis as a novel therapeutic target for idiopathic recurrent pregnancy loss using mesenchymal stem cells.

## Key findings

- MSC treatment increased embryo retention by 190% in a rat model of RPL.
- MSCs upregulated CCR7 and activated NK differentiation pathways in NK92 cells.
- MSCs modulated cytokine profiles by reducing pro-inflammatory markers and increasing IL-10.

## Abstract

Recurrent pregnancy loss (RPL), defined as more than two consecutive miscarriages before 20 weeks of gestation, affects 1%–5% of reproductive‐aged women, with nearly half of the cases remaining idiopathic. Using ethanol‐induced endometrial injury in rats to simulate RPL, we demonstrated that mesenchymal stem cells (MSCs) exert therapeutic effects through two complementary mechanisms: CCR7‐mediated endometrial repair and immunomodulation of uterine natural killer (uNK) cells, compared to ethanol‐induced injury, this treatment achieved a 190% increase in embryo retention (from 2.4 to 7 embryos). Transcriptomic analysis and Western blotting of MSC‐cocultured NK92 cells revealed significant CCR7 upregulation (1.75‐fold increase at the optimal dose of 2 × 104 cells/mL MSCs) and activation of NK differentiation pathways. This was corroborated by immunofluorescence showing enhanced CCR7+ NK cell infiltration in MSC‐treated endometria. MSCs administration altered cytokine profiles by decreasing pro‐inflammatory mediators (IL‐6, TNF‐α, and IL‐1β) and increasing anti‐inflammatory IL‐10 levels simultaneously. Mechanistically, MSCs orchestrate endometrial repair through sequential events: induce the formation of a gradient of CCR7 expression on the endometrial layer and the surface of NK cells; followed by ERK/JNK pathway activation, which promotes CCR7+ uNK cell generation; and finally initiates endometrial proliferation with an increased proportion of Ki67+ cells. Our integrated multi‐omics approach—combining RNA‐Seq, protein analysis, and cytokine profiling—establishes the CCR7‐ERK/JNK axis as a promising therapeutic target, providing clinically relevant parameters for MSCs dosing and administration protocols in idiopathic RPL management.