Abstract
BackgroundThin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms.MethodsEthanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays.ResultsInstilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells.ConclusionOur study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings.Graphical abstract
Highlights
Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage
It is shown that G’ of hyaluronic acid (HA) hydrogel was larger than the corresponding G’’ in the oscillation frequency range of 0.01 to 100 rad/s, indicating that the elasticity of HA hydrogel dominates over its viscosity, which can guarantee the retention and coverage of HA hydrogel in the uterine cavity
Elevated expression of p-Janus Kinase 2 (Jak2) and p-Signal transducer and activator of transcription 5 (Stat5) were observed after exposure to human placenta-derived mesenchymal stem cells (HP-Mesenchymal stem cells (MSCs)) for 24 h. These results proved that HP-MSCs co-culturing could improve the migration of human endometrial glandular cells via the Jak2-Stat5 and c-Fos-vascular endothelial growth factor (VEGF) pathway, providing favorable conditions for endometrial repair
Summary
Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. The implantation rate is still as low as 20–30% due to poor endometrial receptivity [3, 4], among which thin endometrium is a primary cause of failed embryo transfer, resulting in long-term infertility and negative family outcomes. Improving endometrial thickness in patients with thin endometrium will certainly benefit the pregnancy process and achieve positive family outcomes
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