Abstract
BackgroundIntrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium. Although current stem cell treatment options using different types of autologous stem cells have exhibited some beneficial outcomes in IUA patients, the reported drawbacks include variable therapeutic efficacies, invasiveness and treatment unavailability. Therefore, the development of new therapeutic stem cell treatments is critical to improving clinical outcomes.MethodsTwenty-six patients who suffered from infertility caused by recurrent IUA were enrolled in this prospective, non-controlled, phase I clinical trial with a 30-month follow-up. During the procedure, 1 × 107 umbilical cord-derived mesenchymal stromal cells (UC-MSCs), loaded onto a collagen scaffold, were transplanted into the uterine cavity following an adhesion separation procedure. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and the biological molecules related to endometrial proliferation and differentiation were assessed both before and 3 months after cell therapy.ResultsNo treatment-related serious adverse events were found. Three months after the operation, the average maximum endometrial thickness in patients increased, and the intrauterine adhesion score decreased compared to those before the treatment. A histological study showed the upregulation of ERα (estrogen receptor α), vimentin, Ki67 and vWF (von Willebrand factor) expression levels and the downregulation of ΔNP63 expression level, which indicates an improvement in endometrial proliferation, differentiation and neovascularization following treatment. DNA short tandem repeat (STR) analysis showed that the regenerated endometrium contained patient DNA only. By the end of the 30-month follow-up period, ten of the 26 patients had become pregnant, and eight of them had delivered live babies with no obvious birth defects and without placental complications, one patient in the third trimester of pregnancy, and one had a spontaneous abortion at 7 weeks.ConclusionsTransplanting clinical-grade UC-MSCs loaded onto a degradable collagen scaffold into the uterine cavity of patients with recurrent IUA following adhesiolysis surgery is a safety and effective therapeutic method.Trial registrationClinicaltrials.gov. NCT02313415, Registered December 6, 2014.
Highlights
Intrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium
Transplanting clinical-grade umbilical cord-derived mesenchymal stromal cells (UC-MSCs) loaded onto a degradable collagen scaffold into the uterine cavity of patients with recurrent IUA following adhesiolysis surgery is a safety and effective therapeutic method
Flow cytometry analysis showed that the purity of the UC-MSCs was greater than 98%, which was confirmed by the high positive rates of CD105, CD73, CD90 and CD29, while the hematopoietic markers CD45 and CD34 were negative (Additional file 2: Figure S1C)
Summary
Intrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium. The traditional treatment for AS is the transcervical resection of adhesion by hysteroscopy followed by the placement of an intrauterine device, Foley catheter or biomaterials to prevent recurrent intrauterine adhesions (IUA) [3, 4] and hormonal therapy to regenerate the endometrium [5]. In severe cases, the incidence of recurrent IUA was reported to be as high as 62.5% [6]. This endometrial fibrosis impedes embryo implantation [7]. Preventing IUA recurrence and endometrial scarring are considered key factors that affect therapeutic outcomes [8]
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