L26/P-352 Platelet-derived mitochondrial transplantation promotes tissue regeneration by suppressing M1 macrophage polarization in a rat model of endometriosis

Abstract Study question Does platelet-derived mitochondrial (pl-MT) transplantation modulate macrophage polarization toward a less pro-inflammatory phenotype and thereby enhance tissue regeneration in a rat model of endometriosis? Summary answer pl-MT transplantation could shift macrophage polarization toward a less pro-inflammatory phenotype and promote tissue regeneration in a rat model of endometriosis. What is known already Endometriosis is a common, chronic gynecological disorder associated with pelvic pain, infertility, and reduced quality of life. The disease is characterized by a persistent inflammatory microenvironment, in which macrophage polarization toward a pro-inflammatory (M1) phenotype contributes to lesion persistence and impaired tissue repair. Mitochondrial dysfunction has been implicated in dysregulated immune responses in endometriosis. Emerging evidence suggests that mitochondrial transplantation may influence cellular metabolism and inflammatory signaling; however, its effects on macrophage polarization and tissue regeneration in the context of endometriosis have not yet been investigated. Study design, size, duration An experimental animal study was conducted using a rat model of endometriosis induced by subcutaneous autotransplantation of endometrial tissue fragments (4-weeks for lesion establishment). A total of 28 adult female Sprague–Dawley rats were randomly assigned to four groups: Sham (vehicle solution), ShamMit (pl-MT transplantation, 50 µg/200 µL), Endo (vehicle solution), and EndoMit (pl-MT transplantation, 50 µg/200 µL). After lesion establishment, mitochondrial transplantation was performed, and the study was terminated following a 4-week recovery period. Participants/materials, setting, methods pl-MT were isolated and characterized prior to transplantation, and mitochondrial biodistribution was assessed following administration. Endometrial implants were evaluated in vivo using ultrasonography. Inflammatory changes and fibrosis were assessed by hematoxylin and eosin and Masson’s trichrome staining, respectively. Immunohistochemistry was performed for CD38 (M1 macrophages marker), CD10 (stromal cell marker), and ER-α (estrogen receptor alpha). Metabolomics (GC-MS) analyses were performed to assess metabolic alterations associated with mitochondrial transplantation. Main results and the role of chance pl-MT maintained structural integrity and preserved mitochondrial membrane potential (88.5%). Transplanted mitochondria demonstrated biodistribution within ectopic endometrial tissue at 24 hours post-transplantation. Ectopic endometrial implant volume was significantly reduced following pl-MT transplantation, decreasing from 134.34 ± 30.59 mm³ in untreated endometriosis to 78.14 ± 17.27 mm³ after treatment (p < 0.05). Histopathological analyses showed suppression of inflammation and fibrosis, accompanied by reduced CD10, CD38, and ER-α protein expression (p < 0.05), indicating modulation of the inflammatory microenvironment toward a less pro-inflammatory state. Metabolomic profiling revealed a shift toward aerobic glycolysis (Warburg effect) in endometriosis, whereas pl-MT redirected metabolic preference toward oxidative phosphorylation. Limitations, reasons for caution The study assessed a single dose at one post-transplantation time point, and long-term effects and underlying molecular signaling pathways were not evaluated. Wider implications of the findings These findings provide mechanistic insight into mitochondrial regulation of immune and metabolic pathways in endometriosis. pl-MT transplantation represents a novel experimental approach to modulate macrophage polarization and cellular energy metabolism in ectopic endometrial tissue, supporting further investigation of mitochondrial–immune crosstalk in chronic inflammatory disease models. Trial registration number Yes