USING EXOSOMES FOR RESOLVING MARE ENDOMETRITIS
In addition, progesterone level was increased at day 0 of the 3rd ovulation (0.15 ± 0.85) when compared to day −1 before treatment (0.12 ± 0.42), a significant difference was not seen ( p > 0.05).
DISCUSSION
Mesenchymal stem cells were first employed in regenerative medi- cine as a therapy, their efficacy was attributed to the damaged location by direct differentiation, but it has now been discovered that a paracrine signalling is one of the fundamental mechanisms of action (Tetta et al., 2013 ). This communication occurs through neurotransmitters, hormones, chemokines (Morhayim et al., 2014 ) and exosomes. The favourable benefits acquired with secretome are equivalent to those obtained with the cells from which they are produced according to the literature (Aliotta et al., 2007 ; Gatti et al., 2011 ; Lange- Consiglio et al., 2013 ; Sabry et al., 2018 ). The regenerative mechanism of stem cells has recently been
focused on exosomal activity, which is essential for horizontal cy- toplasm content transfer (Lange Consiglio et al., 2018 ). After treat- ment with exosomes derived from bone marrow- derived MSCs, our histological study revealed enhanced epithelial thickness, re- epithelisation and the number of blood vessels in the wound areas. Angiogenesis is required for the restoration of blood flow and the repair of injured skin wounds (Li et al., 2003 ) as arteries deliver nutri- tion, soluble factors, oxygen and circulating stem or progenitor cells to wounded tissues, allowing tissue regeneration to continue. More- over, the angiogenesis process was enhanced after treatment by histological evaluations (Gavalas et al., 2013 ; Reynolds et al., 2002 ). The elevation of blood flow rate and peak systolic velocity in this study after treatment with the presence of positive pregnancy di- agnosis may be due to the vasoactive factors effect that sought by pre- implanted embryos (Esteller- Vico et al., 2015 ; Silva et al., 2005 ). Post- treatment histopathological results showed an enhancement in the classification of endometritis, confirming the effectiveness of exosomal intrauterine infusion. The mare was judged as normal at the end of treatment with successful embryo scanning at days 14 and 20 following AI. Overall, our results suggested that the more pronounced activity of exosomes that was essential for accelerating angiogenesis process and treating the endometritis, whereas it plays important roles in the re- epithelisation process (Yang et al., 2015 ), maintain the reproductive cycle and the endometrium regenerates under the influence of ovarian oestradiol (Jabbour et al., 2006 ). En- dometrial mesenchymal cells and endothelial stem cells of the endo- metrium were identified uterine stem cell population as previously reported by Zuo et al. ( 2018 ). These multipotent cells play an im- portant role in endometrial function and display stem cell- specific surface markers (Cervello et al., 2011 ) with their regeneration ability is thought to be critical for the human endometrium throughout re- productive cyclicity (Gargett et al., 2012 ). Mesenchymal stem cells have the ability to heal injured endo-
metrial stromal cells and develop into endometrial epithelial cells and stimulate endometrial epithelial cell differentiation (Chen
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et al., 2019 ). MSCs trigger repair processes by releasing hormones such as insulin- like growth factor, and vascular endothelial growth factor (VEGF). Similar to our study, in rats suffering from endometrial injuries that were treated by microvesicles (MVs) derived from bone marrow transplantation (Koippallil et al., 2017 ). MVs moved to the damaged areas and released growth factors, resulting in increased endometrial and muscle layer cellular proliferation. Furthermore, MSC growth factors can help in the microvasculature regeneration, implantation and embryonic development were shown to trigger the repair of injured endometrium in another investigation, resulting in the restoration of fertility (Zhang et al., 2018 ). This evidence corroborates our original idea concerning exo-
somes being able to heal both the wounded and damaged endo- metrium and the correct communication required for successful embryo implantation. This is the first report to discuss Arabian mares with chronic degenerative endometritis and a history of failed insemination that seemed to be cured after intrauterine delivery of exosomes secreted in vitro by bone marrow MSCs. In this scenario, it is reasonable to conclude that the activity of exosomes triggered tissue regeneration with a return to original histologic features lead to normal endometrial function by restoring normal blood flow in this mare. This most likely restored the circumstances essential for proper development and implantation, such as maternal– embryonic paracrine
communication. In cows with induced endometritis,
Doppler ultrasonography revealed a significant increase in uterine flow (Debertolis et al., 2016 ).
In this investigation, therapy using
exosomes resulted in a significant decrease in oestrogen and a rise in progesterone, which was consistent with endometritis as an in- crease in oestradiol was found, as previously described (Abdelnaby, Emam, Salem, et al., 2020 ; Janowski et al., 2013 ). The increased uterine pulsatility index (PI) might be due to a decrease in arterial velocity (Abdelnaby, 2020b ; Abdelnaby, Abouelela, & Yasin, 2021 ; Maher et al., 2020 ), while the decreased uterine PI could be due to a significant increase in blood peak and end velocities (Abouelela et al., 2021 ; Ferreira et al., 2008 ). In this context, it is reasonable to conclude that the activity of exosomes and the miRNAs contained in them triggered tissue regeneration in this mare, resulting in a res- toration to the original histological features and thus, normal endo- metrial function. This likely restored the circumstances essential for proper development and implantation of maternal– embryonic para- crine communication.
CONCLUSION
We conclude that severe injuries occurred in endometrium can lead to endometrial fibrosis and thin endometrium which affect the fer- tility age in Arabian mares depending on the degree of injury. How- ever, due to the uterine environments and function ' s complexity, effective therapy options are limited. As a result, new therapy strat- egies to heal endometrial damage restore its microenvironment and tolerance status, and increase the conception rate in infertile mares are urgently needed in reproductive technology.
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