Presently, according to reports, 2.8%-45.5% of women with IUA have impaired fertility, notably occurring after pregnancy-related dilatation and curettage in more than 90% of cases [5, 6]. Up to now, lUA has been treated mainly with both surgical and estrogenic modalities, and unfortunately, the recurrence rate is high, ranging from 20–63% [3]. Additionally, there is also a high risk for placental implantation. Therefore, it is particularly important to develop safe and feasible treatment options for patients with lUA at this time.
Mesenchymal stem cells have now been widely used for tissue repair.Gargett et al. proposed that LUA patients could reconstruct endometrial tissue with endometrial mesenchymal stem cells [1]. Nagori et al. showed that bone marrow mesenchymal stem cell transplantation was effective in promoting repair of damaged endometrium in vivo [22], a view shared by Phermthai et al. Mesenchymal stem cell transplantation has been reported to be effective in repairing endometrial defects such as infertility and endometrial hyperplasia [23, 24]. In fibrotic diseases, mesenchymal stem cells play an anti-fibrotic role, for example, pulmonary fibrosis, renal fibrosis and hepatic fibrosis can be treated with mesenchymal stem cells [25–29]. One of the typical representatives of ECM is the submucosa of the small intestine (SIS), such as skin, bone, bladder, ligaments, and abdominal wall, which has been widely used for tissue repair and clinical trials [13].After SF coating by a single-component LbL assembly, the SIS membrane exhibited good cell compatibility and are not only well resistant to rapid degradation, but also maintain structural integrity [20]. In this study, We seeded HuMSCs on the surface of the SF-SIS scaffold and were surprised to find an increase in the number of HuMSCs-seeded SF-SIS scaffold glands, as well as a reduction in the fibrotic area of the lUA model. Based on the study data, we conclude that HuMSC-seeded SF-SIS scaffolds may be used for IUA treatment.
CircRNAs are circular non-coding RNAs that are resistant to the digestive action of RNase R. CircRNAs are mainly made by selective splicing (post splicing) of information exchange between upstream splice acceptors and downstream splice donors [30, 31]. Our comparison of circRNAs with long-stranded noncoding RNAs (IncRNAs) and microRNAs (miRNAs) in mammalian cells revealed that circRNAs are better in terms of stability and conservation[32]. Meanwhile, circRNA can interfere with the expression of related genes, transcribe and interfere with RNA responses, and also act as a scaffold or template to assemble or synthesize protein complexes through circRNA sponge action [33].Recent reports have confirmed the role of several functional circRNAs in regulating tissue regeneration of MSCs. For example, the pluripotency of human embryonic stem cells (hESCs) is maintained by sponge transfection of circBIRC6 with miR-34a and miR-145 [34]. CircHIPK3 has been reported to promote a variety of cancers by absorbing multiple miRNAs through sponge uptake [35]. CircSMARCA5 inhibits glioblastoma pleomorphic cell migration but facilitates prostate cancer cell proliferation [36]. In this study, we found that circPTP4A2 is critical to HuMSCs-SF-SIS increasing the number of glands and decreasing the fibrosis area in the lUA model by targeting miR-330-5p-PDK2 signaling.
A distinctive feature of eukaryotic cells is the presence of intracellular mitochondria, which play an important role in energy metabolism and apoptosis and are essential in biological longevity[37]. In cells, mitochondria carry out complex biological reactions and are one of the most complex reactive sensing systems [38]. Recent studies have shown that balancing mitochondrial dynamics, which regulate the fate of stem cells, and morphology is crucial for maintaining tissue homeostasis[39]. Recent studies have found that mitochondrial metabolism can be significantly altered by environmental stimuli [40]. An important feature of the MSC niche is hypoxia, which has been shown over the last decade to have a key role in maintaining three aspects of stem cell survival, self-replication and pluripotency [41]. It was found that for the glycolytic pathway, transcription and synthesis of enzymes increased in hypoxic cells, but synthesis of proteins involved in mitochondrial catabolism decreased [42].The proliferation, differentiation and survival of BMSCs has been shown to be affected by culture under hypoxic pressure[43]. Cytochrome oxidase, an enzyme located at the end of the mitochondrial respiratory chain, is involved in aerobic synthesis in mammalian cells, mainly using oxygen as a substrate [27]. Under hypoxic conditions, mitochondrial size and average velocity were significantly reduced [44]. In this study, we found that circPTP4A2-miR-330-5p-PDK2 signaling is critical for the stability of mitochondrial metabolism in HuMSCs under hypoxic conditions. Collectively, we constructed HuMSC-seeded SF-SIS scaffolds and evaluated the impact of repairing damaged endometrium in an lUA mouse model. Interestingly, we performed an in-depth study of the underlying mechanisms of endometrial repair progression in HuMSCs, in which circPTP4A2 is elevated in the HuMSCs seeded on the SF-SIS scaffolds and stabilizes mitochondrial metabolism via miR-330-5p-PDK2 signaling. Furthermore, these findings demonstrated that HuMSC-seeded SF-SIS scaffolds signify future clinical applications in the treatment of lUA.