Therapeutic Effect of Human Amniotic Epithelial Cells in Rat Models of Intrauterine Adhesions

Abstract

As a refractory fibrosis disease, intrauterine adhesions (IUAs) is defined as fibrosis of the physiological endometrium. Although hysteroscopic adhesiolysis is widely recommended as an effective treatment, prognosis and recurrence remain poor in severe cases. Recently, stem cell therapy has been promoted as a promising treatment for IUAs. The ability of human amniotic epithelial cells (hAECs), emerging as a new candidate for stem cell therapy, to treat IUAs has not been demonstrated. To study the potential effects of hAECs on IUAs, we created an IUA rat model using mechanical injury and injected cultured primary hAECs into the rats’ uteri. Next, we observed the morphological structure of endometrial thickness and glands using hematoxylin and eosin staining, and we detected extracellular-matrix collagen deposition using Masson staining. In addition, we performed immunohistochemical staining and reverse-transcription polymerase chain reaction (RT-PCR) to investigate potential fibrosis molecules and angiogenesis factors 7 d after hAECs transplantation. Finally, we detected estrogen receptor (ER) and growth factors via RT-PCR to verify the molecular mechanism underlying cell therapy. In the IUA rat models, endometrial thickness and endometrial glands proliferated and collagen deposition decreased significantly after hAEC transplantation. We found that during the recovery of injured endometrium, the crucial fibrosis marker transforming growth factor-β (TGF-β) was regulated and angiogenesis occurred in the endometrial tissue with the up-regulation of vascular endothelial growth factor. Furthermore, hAECs were shown to promote ER expression in the endometrium and regulate the inflammatory reaction in the uterine microenvironment. In conclusion, these results demonstrated that hAEC transplantation could inhibit the progression of fibrosis and promote proliferation and angiogenesis in IUA rat models. The current study suggests hAECs as a novel stem cell candidate in the treatment of severe IUA.

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.…”

MiR-543 Inhibits the Migration and Epithelial-To-Mesenchymal Transition of TGF-β-Treated Endometrial Stromal Cells via the MAPK and Wnt/β-Catenin Signaling Pathways

“…Furthermore, numerous studies have indicated that transforming growth factor (TGF)-β is a cytokine that participates in regulating diverse biological functions, including cell proliferation, apoptosis, and differentiation [ 11 , 12 ]. Importantly, previous studies have reported that TGF-β can induce endometrial fibrosis [ 13 , 14 ] and TGF-β treated ESC can serve as the in vitro model of IUA [ 15 , 16 ].…”

Concentrated small extracellular vesicles from menstrual blood-derived stromal cells improve intrauterine adhesion, a pre-clinical study in a rat model

“…39 The upregulation in the expression of the inflammation-related profibrotic molecule TGFβ1 has been shown to be positively correlated with the degree of IUA both in clinical endometrial samples and animal models. [40][41][42] Increased TGFβ1 expression is believed to be directly related to the occurrence and development of fibrosis, which may aggravate endometrial fibrosis through the SMAD3 signaling pathway. 43,44 Yao et al reported that BMSC-derived EVs reversed endometrial fibrosis via inhibiting TGFβ1 activation and EMT in vitro.…”