Inflammatory Response to Menstrual Fluid Does Not Induce Fibrotic Morphogenesis Program in Human Endometrial Stromal Cells

INTRODUCTION: Human endometrium is one of peculiar tissues capable of scarless regeneration after injury during every menstrual cycle, birth, or surgery. However, it is disputable whether this feature should be attributed to specific regulatory factors of wound environment and menstrual fluid (MF) or to tissue-specific properties of endometrial mesenchymal stromal cells (eMSCs), which are pivotal participants of wound healing. We aimed to elucidate the role of eMSC tissue specificity in wound healing. METHODS: We evaluated changes of eMSC transcriptomic profile in response to MF and their potency to granulation tissue formation in vitro in comparison with those of stromal cells from scar-forming organs - dermal and adipose MSC (dMSC and adMSC). RESULTS: We have found that MF contains numerous inflammatory factors and induces a profound inflammatory response in both eMSC and dMSC, but a tissue-specific component was identified in their transcriptome profiles. Furthermore, transcriptomic tissue specificity was stable and present prior to MF treatment as well as after it, so we validated our findings against in vivo single-cell RNA-sequencing data from Human Protein Atlas. Tissue specificity traits were related to embryonic development and morphogenesis, suggesting a putative contribution of "developmental imprinting" in its establishment. Using in vitro models of fibroplasia, angiogenesis, and extracellular matrix deposition, we showed that eMSC lack the ability to induce these processes in contrast to dMSC and adMSC. Finally, we refined transcription factors (TFs) from stable tissue-specific genes that may explain the unique properties of eMSC and endometrium itself and can serve as potential targets to induce regeneration in scar-forming organs. CONCLUSION: eMSCs possess tissue-specific properties including stable expression of TFs that may explain the scarless regeneration of endometrium.