Abstract
BackgroundSevere 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.MethodsIn 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.ResultsThe 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).ConclusionsThe 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.
Highlights
Severe injuries of the uterus may trigger uterine scar formation, leading to infertility or obstetrical complications
The scaffold/Umbilical cord-derived mesenchymal stem cells (UC-Mesenchymal stem cells (MSCs)) system facilitated collagen degradation in uterine scars via upregulation of matrix metalloproteinase-9 antibody (MMP-9), which was secreted by transplanted UC-MSCs, and promoted regeneration of the endometrium, myometrium and blood vessels in uterine scars
As shown in Additional file 1: Figure S1, 128 scarred uterine horns from 64 rats were randomly assigned to four groups, including a phosphate-buffered saline (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
Summary
Severe injuries of the uterus may trigger uterine scar formation, leading to infertility or obstetrical complications. When severe uterine traumas caused by caesarean section, curettage, myomectomy or infection impair the basalis of the endometrium, a loss of resident stem cells and the stem cell niche will take place. This triggers the excessive activation of fibroblasts and the subsequent continuous secretion of collagen, leading to formation of uterine scars. Excessive collagen deposition can impede the proliferation, differentiation and migration of uterine native cells, so the impaired uterine wall, especially the endometrium, presents collagenous scars [6, 7]. Uterus factor infertility, recurrent miscarriage, placenta accreta and intrauterine growth restriction may take place [8,9,10,11]
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