Abstract
BackgroundIntrauterine adhesion (IUA) is a major cause of female secondary infertility. We previously demonstrated that menstrual blood-derived stromal cell (MenSC) transplantation helped severe IUA patients have pregnancy and endometrium regeneration. We also initiated platelet-rich plasma (PRP) acted as a beneficial supplement in MenSC culturing and a potential endometrial receptivity regulator. Here, we investigated the therapeutic effect of combined transplantation of MenSCs with PRP in rat IUA models and the mechanisms of MenSCs in endometrium regeneration.MethodsRat IUA models were established by intrauterine mechanical injured. Nine days later, all rats were randomly assigned to four groups received different treatment: placebo, MenSC transplantation, PRP transplantation, and MenSCs + PRP transplantation. The traces of MenSCs were tracked with GFP label. Endometrial morphology and pathology, tissue proliferation, inflammation, pregnancy outcomes, and mechanism of MenSCs in the regeneration of endometrium were investigated.ResultsNotably, at days 9 and 18 post-treatment, MenSC transplantation significantly improved endometrial proliferation, angiogenesis, and morphology recovery and decreased collagen fibrosis and inflammation in the uterus. MenSCs had lesion chemotaxis, colonized around the endometrial glands. Gene expression of human-derived secretory protein IGF-1, SDF-1, and TSP-1 was detected in the uterus received MenSCs at day 18. The three treatments can all improve fertility in IUA rats. Moreover, gene expressions of cell proliferation, developmental processes, and other biological processes were induced in MenSC transplantation group. Hippo signaling pathway was the most significantly changed pathway, and the downstream factors CTGF, Wnt5a, and Gdf5 were significantly regulated in treatment groups. PRP enhanced these parameters through a synergistic effect.ConclusionsIn summary, MenSCs could effectively improve uterine proliferation, markedly accelerate endometrial damage repairment and promote fertility restoration in IUA rats, suggesting a paracrine restorative effect and Hippo signaling pathway stimulation. Our results indicate MenSCs, a valuable source of cells for transplantation in the treatment intrauterine adhesion. Combined with PRP, this cell therapy was more effective.
Highlights
Intrauterine adhesion (IUA) is a major cause of female secondary infertility
Location of menstrual blood-derived stromal cells (MenSCs) in the endometrium in rat IUA model Due to the ethical restriction related to the human specimen, rat IUA model was established according to previous reports to clarify the mechanism underlying MenSCs and platelet-rich plasma (PRP) transplantation in endometrium restoration [18, 19]
Eighteen days after injection of MenSCs (n = 6) into the right lateral uterus, a clear fluorescent signal was observed in bilateral uteri and ovaries, while the signal was rarely seen in other major organs including the brain, heart, and liver
Summary
We previously demonstrated that menstrual blood-derived stromal cell (MenSC) transplantation helped severe IUA patients have pregnancy and endometrium regeneration. We investigated the therapeutic effect of combined transplantation of MenSCs with PRP in rat IUA models and the mechanisms of MenSCs in endometrium regeneration. Several studies have demonstrated the existence of an adult stem cell population capable of regenerating endometrial tissue, its circulatory origin cannot be ruled out [5, 6]. Supplementing stem cells from the uterus or other tissues is one of the research hotspots for endometrium regeneration. With their capability to integrate into the injured tissues, bone marrow-derived stem cells (BMSCs) are commonly used for cell therapy [7, 8]. A less invasive source of stem cell needs to be investigated
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