Intrauterine 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. Twenty-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. No 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. Transplanting 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. Clinicaltrials.gov . NCT02313415 , Registered December 6, 2014.

Severe injuries of the uterus may trigger uterine scar formation, ultimately leading to infertility or obstetrical complications. To date, few methods have adequately solved the problem of collagen deposition in uterine scars. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have shown great promise in clinical applications. The objective of this study was to investigate the effect of a scaffold/UC-MSCs construct on collagen degradation and functional regeneration in rat uterine scars following full-thickness excision of uterine walls. In order to establish a rat model of uterine scars, the uterine wall of approximately 1.0 cm in length and 0.5 cm in width (one-third of the uterine circumference) was excised from each uterine horn. A total of 128 scarred uterine horns from 64 rats were randomly assigned to four groups, including a PBS group (n = 32 uterine horns), scaffold group (n = 32 uterine horns), UC-MSCs group (n = 32 uterine horns) and scaffold/UC-MSCs group (n = 32 uterine horns) to investigate the effect of different treatments on the structure and function of uterine scars. PBS, degradable collagen fibres, UC-MSCs or UC-MSCs mixed with gelatinous degradable collagen fibres were injected into four pre-marked points surrounding each uterine scar, respectively. At days 30 and 60 post-transplantation, a subset of rats (n = 8 uterine horns) from each group was euthanized and serial sections of uterine tissues containing the operative region were prepared. Haematoxylin-eosin staining, Masson’s trichrome staining, and immunohistochemical staining for MMP-2, MMP-9, α-SMA and vWF were performed. Finally, another subset of rats (n = 16 uterine horns) from each group was mated with male rats at day 60 post-transplantation and euthanized 18 days after the presence of vaginal plugs to check numbers, sizes and weights of fetuses, as well as sites of implantation. The scaffold/UC-MSCs group exhibited obvious collagen degradation compared with the other three groups. At day 60 post-transplantation, the number of MMP-9-positive cells in the scaffold/UC-MSCs group (25.96 ± 3.63) was significantly higher than that in the PBS group (8.19 ± 1.61, P < 0.01), the scaffold group (7.25 ± 2.17, P < 0.01) and the UC-MSCs group (8.31 ± 2.77, P < 0.01). The pregnancy rate in the scaffold/UC-MSCs group (10/16) was also significantly higher than that in the PBS group (2/16, P < 0.017), the scaffold group (1/16, P < 0.017) and the UC-MSCs group (3/16, P < 0.017). The scaffold/UC-MSCs system facilitated collagen degradation in uterine scars via upregulation of MMP-9, which was secreted by transplanted UC-MSCs, and promoted regeneration of the endometrium, myometrium and blood vessels in uterine scars. Furthermore, the scaffold/UC-MSCs-treated uterine scars showed nearly complete restoration of receptive fertility.