Extracellular vesicle-packaged PKM2 from endometriotic stromal cells promotes endometrial collagen I deposition by inhibiting autophagy in endometriosis.

Aberrant endometrial collagen I deposition during the implantation window impairs endometrial stromal cell (ESC) decidualization, which may contribute to lower pregnancy rate in endometriosis (EMs) patients with in vitro fertilization (IVF) treatment. However, the underlying mechanism of eutopic aberrant endometrium collagen I deposition in EMs remains unclear. In this study, we found increased endometrial collagen I and defective decidualization in the mid-secretory phase of EMs patients, while the level of eutopic ESCs' autophagy was decreased, which was an important mechanism of intracellular collagen degradation. Lower ESCs' autophagy level may cause the endometrial collagen I deposition in EMs. Furthermore, in vivo and in vitro studies showed that the extracellular vesicles derived from the ectopic ESCs of EMs patients (EMs-EVs) encapsulated higher PKM2 inhibited autophagy of the ESCs accompanied by an increase of collagen I. We also found that the constructed EMs-EVsAd-PKM2 with PKM2 overexpression inhibited ESCs' autophagy by activating the Akt/mTOR signaling pathway. And the expressions of PKM2, p-Akt and p-mTOR were also increased in the endometrium of EMs patients. Collectively, these data showed that EMs-EVs delivering PKM2 inhibited autophagy inducing aberrant endometrial collagen I deposition via the Akt/mTOR signaling pathway to impair decidualization, which provided a potential therapeutic target for improving the IVF pregnancy rate in EMs patients.