Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we est...Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we established an endometrial assembloid model that faithfully mimics cycle-dependent endometrial responses and captures key cellular and molecular hallmarks of adenomyosis,including ectopic lesionspecific epithelial and stromal heterogeneity.Single-cell transcriptomics revealed that ectopic epithelial cells shift toward a luminaldominant,glandular-deficient transcriptional profile during the secretory-like phase.This transition correlated with ectopic stromal reorganization—specifically,loss of BMP4^(+)stromal cells and an accumulation of CRYAB^(+)IL15^(+)stromal cells—which impaired BMP-mediated stromal-epithelial signaling while enhancing WNT activation.Additionally,ectopic epithelial and stromal cells demonstrated increased immunity and angiogenesis activities.Our assembloid platform not only provides a physiologically relevant model for investigating adenomyosis pathogenesis but also implicates aberrant WNT signaling as a potential therapeutic target,offering new opportunities for mechanism-driven treatment strategies.展开更多
Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endom...Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just beginning.Using single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and EMJ.Within lesions,we identified unique epithelial(LGR5+)and invasive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between“invagination”and“metaplasia”theories of pathogenesis.Further,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways.Cell-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT cascades.This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.展开更多
基金supported by the National Natural Science Foundation of China(82488101 to S.G)the National Natural Science Foundation of China(82471684 to X.C.,32330030 to S.G.,32270840 to L.W.,32270908 to X.X.)+3 种基金the National Key Research and Development Program of China(2023YFA1800300 to X.X.,2023YFA1801800 to L.W.,2022YFC2702200 to S.G.)Science and Technology Commission of Shanghai Municipality(23JC1403700)Shanghai Key Laboratory of Maternal-Fetal Medicine(mfmkf202201)the Natural Science Foundation of Zhejiang Province(LTGY24H040002)。
文摘Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we established an endometrial assembloid model that faithfully mimics cycle-dependent endometrial responses and captures key cellular and molecular hallmarks of adenomyosis,including ectopic lesionspecific epithelial and stromal heterogeneity.Single-cell transcriptomics revealed that ectopic epithelial cells shift toward a luminaldominant,glandular-deficient transcriptional profile during the secretory-like phase.This transition correlated with ectopic stromal reorganization—specifically,loss of BMP4^(+)stromal cells and an accumulation of CRYAB^(+)IL15^(+)stromal cells—which impaired BMP-mediated stromal-epithelial signaling while enhancing WNT activation.Additionally,ectopic epithelial and stromal cells demonstrated increased immunity and angiogenesis activities.Our assembloid platform not only provides a physiologically relevant model for investigating adenomyosis pathogenesis but also implicates aberrant WNT signaling as a potential therapeutic target,offering new opportunities for mechanism-driven treatment strategies.
基金National Natural Science Foundation of China(Nos.32270840,31721003 and 32270908)Shanghai Key Laboratory of Maternal Fetal Medicine(No.mfmkf202201)+1 种基金Natural Science Foundation of Zhejiang Province(No.LTGY24H040002)Jiaxing Municipal Public Welfare Research Project(No.2021AY30004).
文摘Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding“invagination”and“metaplasia”theories.The endometrial-myometrial junction(EMJ)connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just beginning.Using single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and EMJ.Within lesions,we identified unique epithelial(LGR5+)and invasive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between“invagination”and“metaplasia”theories of pathogenesis.Further,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways.Cell-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT cascades.This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.
