Exosomal MiR-381 from M2-polarized macrophages attenuates urethral fibroblasts activation through YAP/GLS1-regulated glutaminolysis

Chen, Ye‐Hui; Xu, Yicheng; Lin, Tingting; Chen, Hang; Dong, Ru‐Nan; Cai, Fen; Ke, Zhi‐Bin; Chen, Jia-Yin; Wei, Yong; Zheng, Qing‐Shui; Xue, Xue-Yi; Xu, Ning

doi:10.1007/s00011-023-01735-x

Cited by 3 publications

(1 citation statement)

References 37 publications

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“…When the Hippo pathway is inhibited, YAP/TAZ translocates into the nucleus and binds to the transcription factor TEAD to activate the transcription of target genes, thereby regulating the function of target cells [ 20 , 21 ]. YAP has been reported to be associated with fibrotic processes in various organs such as the urinary tract and liver, YAP has also played an important role in scar-free repair of the endometrium during menstruation [ 22 – 24 ]. An in vitro study showed that MenSCs inhibited fibroblast activation and attenuated endometrial fibrosis by activating the Hippo pathway through paracrine effects [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination

Qi,

Zhang,

Zhang

et al. 2023

J Nanobiotechnol

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Background Intrauterine adhesion (IUA) is a recurrent and refractory reproductive dysfunction disorder for which menstrual blood-derived stromal cells (MenSCs) might be a promising intervention. We reported that administration of MenSCs-derived exosomes (MenSCs-EXO) could achieve similar therapeutic effects to MenSCs transplantation, including alleviating endometrial fibrosis and improving fertility in IUA rats. The mass spectrometry sequencing result suggested that UBR4, a member of the proteasome family, was abundantly enriched in MenSCs-EXO. This study aimed to investigate the key role of UBR4 in MenSCs-EXO for the treatment of IUA and the specific molecular mechanism. Results UBR4 was lowly expressed in the endometrial stromal cells (EndoSCs) of IUA patients. MenSCs-EXO treatment could restore the morphology of IUA endometrium, reduce the extent of fibrosis, and promote endometrial and vascular proliferation. Knockdown of UBR4 in MenSCs did not affect the characteristics of exosomes but attenuated the therapeutic effect of exosomes. UBR4 in MenSCs-EXO could alleviate endometrial fibrosis by boosting YAP ubiquitination degradation and promoting YAP nuclear-cytoplasmic translocation. Moreover, P65 could bind to the UBR4 promoter region to transcriptionally promote the expression level of UBR4 in MenSCs. Conclusion Our study clarified that MenSCs-EXO ameliorated endometrial fibrosis in IUA primarily by affecting YAP activity mediated through UBR4, while inflammatory signaling P65 may affect UBR4 expression in MenSCs to enhance MenSCs-EXO therapeutic effects. This revealed a novel mechanism for the treatment of IUA with MenSCs-EXO, proposing a potential option for the clinical treatment of endometrial injury.

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