Combined spermidine and umbilical cord mesenchymal stem cell therapy repairs endometrial injury in mice via IL-10/Treg-Dependent immune microenvironment modulation.

The aim of the present study was to explore the reparative effects of spermidine combined with umbilical cord mesenchymal stem cells (UC-MSCs) on endometrial injury in mice. First, bioinformatic results suggested that endometrial damage is closely linked to immune mechanisms, a finding that was corroborated by quantitative polymerase chain reaction results. Next, an endometrial injury model was established by injecting 95% ethanol into the uterus, and spermidine combined with UC-MSCs was used for treatment. We found that the combination of spermidine and umbilical cord mesenchymal stem cells (S+UC-MSCs) significantly reduced CD36 expression while significantly increasing the expression of the proteins THBS2, TIMP3, CLU, and CFH. In addition, S + UC-MSCs significantly increased the number of Tregs and the protein levels of interleukin-4 (IL-4) and interleukin-10 (IL-10), whereas the protein levels of interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and interleukin-17 (IL-17) decreased significantly. Furthermore, S + UC-MSCs also improved the morphology of mouse endometria by regulating angiogenesis (microvessel density [MVD] and vascular endothelial growth factor [VEGF]) and receptivity (HOXA10, LIF, LPAR3, and αvβ3). These results indicated that the combined therapy of spermidine and UC-MSCs promotes angiogenesis, enhances uterine receptivity, regulates the IL-10/Treg-mediated immune microenvironment to restore endometrial morphology, and shows a tendency to increase the pregnancy rate in mice.