Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0535-0) contains supplementary material, which is available to authorized users.

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…It has been suggested that matrix metalloproteinases (MMPs) might play a prominent role in reducing scar size upon SC transplantation. Administration of MSCs in fibrotic liver or uterine tissue was associated with lower collagen deposition and significantly increased levels of MMP-9 [370,371]. Rising levels of MMPs in tissue were also described in SC-mediated cardiac repair.…”

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

“…Moreover, stem cells produce several anti‐inflammatory and antifibrotic mediators, and secrete factors that create a regenerative microenvironment . Cord blood stem cells embedded in a scaffold secrete for example MMP‐9, mediating collagen degradation in uterine scars, which improves the regeneration of the endometrium, myometrium and blood vessels . Administered cord blood stem cells also promote the recruitment of endogenous stem cells …”

“…[130][131][132][133] Cord blood stem cells embedded in a scaffold secrete for example MMP-9, mediating collagen degradation in uterine scars, which improves the regeneration of the endometrium, myometrium and blood vessels. 134 Administered cord blood stem cells also promote the recruitment of endogenous stem cells. 135,136 The isolation of MSCs from bone marrow or adipose tissue from the baby is rather invasive and can cause complications such as infection, bleeding, and chronic pain.…”

“…Direct injection of cord blood stem cells into a wound site is not always effective. 134 In muscle tissue, isolated stem cells can be applied to the site of injury to improve regeneration. 161 However, the success rate after isolation and injection of stem cells has been low.…”

Leukemia inhibitory factor promotes the regeneration of rat uterine horns with full‐thickness injury

“…Severe uterine traumas caused by caesarean section, myomectomy, curettage or hysteroscopic incision of the uterine septum can lead to scar formation, which affects the normal function of the uterus and potentially resulting in recurrent miscarriage, placenta accreta, uterine rupture, or infertility . Significant efforts have been made to repair the uterus after damage . However, there are few effective methods to restore the structure and function of a severely damaged uterus.…”