Human amniotic epithelial cells improve fertility in an intrauterine adhesion mouse model

Abstract

Background Intrauterine adhesion (IUA) is an adhesion of the uterine cavity or cervical canal resulting from damage to the basal layer of the endometrium; this condition is usually accompanied by fibrosis of the endometrium. Previous studies have demonstrated that human amniotic epithelial cells (hAECs) have stem cell characteristics; however, it is unclear whether hAECs have the therapeutic potential to restore fertility after IUA. Methods A murine IUA model was established by mechanical injury to the uterus. Then, 10 6 hAECs were transplanted by intraperitoneal injection. The endometrium thickness, number of glands, and fibrosis area were measured by hematoxylin and eosin (H&E) staining and Masson staining. Molecules (including vWF, VEGF, PCNA, ER, PR, LC3, and p62) related to endometrial angiogenesis, cell proliferation, and autophagy were assayed by IHC staining. Pregnancy outcomes were also evaluated. Finally, hAECs were cocultured with human endometrial mesenchymal stem cells (hEnSCs) damaged by H 2 O 2 to verify the paracrine effect on endometrial stromal cells in vitro. Results The IUA uterine cavity presented with adhesion and even atresia, accompanied by a thinner endometrium, fewer glands, increased fibrosis area, and fewer microvessels. However, hAECs significantly improved the uterine structure after IUA. After hAEC treatment, the endometrium was thicker, the number of endometrial glands was increased, fibrosis was reduced, and more microvessels were generated. The expression levels of VEGF, PCNA, and ER were increased in the hAEC-treated endometrium, indicating improvements in angiogenesis and stromal cell proliferation. hAECs also increased pregnancy outcomes in IUA mice, and the pregnancy rate and fetus number increased. Furthermore, we observed altered autophagy in the IUA uterine model, and hAEC transplantation upregulated autophagy. An in vitro study showed that hAECs activated autophagy in (hEnSCs) treated with H 2 O 2 in a paracrine manner. Conclusions Our results demonstrated that hAECs have the potential to repair the uterus after injury, providing a new strategy for the prevention and treatment of Asherman syndrome.

Quantification of the CM-Dil-labeled human umbilical cord mesenchymal stem cells migrated to the dual injured uterus in SD rat

“…The injury of normal endometrium in IUAs makes the epithelial cells and interstitial glandular cells rich in ERα disappear; however, the expression of ERα in the basal layer and even SM layer is relatively less, resulting in the trauma site that is not sensitive to estrogen stimulation. Some recent studies have confirmed that the expression of ER in the endometrial tissue of IUAs is significantly decreased [18,29].…”

“…Among these MSCs, hUC-MSCs are preferred in that they can be collected easily, non-invasive, and no ethical constraints; they can secrete various cytokines and trophic factors; and they are immunoprivileged [ 9 , 10 ]. About IUAs, the current studies tend to focus on the efficacy of MSCs [ 17 , 18 ]. However, studies on the distribution of hUC-MSCs in the uterus of IUAs after cell transplantation are far from well elucidated.…”

Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications

“…Based on their plasticity and immunomodulatory properties, hAESCs have been considered for treatment of a broad variety of conditions, including lung fibrosis [ 40 , 115 , 131 , 149 , 151 , 152 , 153 , 154 ], spinal cord injuries [ 60 ], Parkinson’s disease [ 64 ], Alzheimer’s disease [ 155 ], diabetes [ 69 ], wound healing [ 147 , 148 , 156 ], liver fibrosis [ 75 , 157 , 158 , 159 ], autoimmune uveitis [ 135 ], Hashimoto’s thyroiditis and systemic lupus erythematosus [ 134 ], and intrauterine adhesions [ 160 , 161 , 162 ]. Among these preclinical trials involving hAESCs, autoimmune diseases make up a large proportion, presumably because of the tremendous effect of immunomodulation.…”

Application of human amniotic epithelial cells in regenerative medicine: a systematic review

“…As promising seed stem cell, hAECs have been widely used to treat various diseases through transplantation therapy. Evidence supported by animal studies has revealed that hAECs show therapeutic potential for treatment of many diseases, including neurological disorders [ 1 – 4 ], lung injury [ 5 , 6 ], liver injury [ 7 ], diabetes [ 8 ], acute kidney failure [ 9 ], cardiovascular diseases [ 10 ], wound healing [ 11 ], healing of stage III pressure ulcers [ 12 ], intrauterine adhesion [ 13 ], and premature ovarian failure (POF) [ 14 ]. Although hAECs have exhibited good therapeutic efficacy, they possess differences in differentiation potential, secretory function, and immunomodulatory activity under different conditions, producing specific effects depending on their application.…”