Organoid co-culture model of the human endometrium in a fully synthetic extracellular matrix enables the study of epithelial-stromal crosstalk.
Organoid co-culture model of the human endometrium in a fully synthetic extracellular matrix enables the study of epithelial-stromal crosstalk.
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在完全合成的细胞外基质中人类子宫内膜的类器官共培养模型使得上皮-间质串扰的研究成为可能。
DOI：
10.1016/j.medj.2023.07.004
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Griffith,LindaG
中科院分区：
文献类型：
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作者：
Gnecco,JuanS;Brown,Alexander;Buttrey,Kira;Ives,Clara;Goods,BrittanyA;Baugh,Lauren;Hernandez-Gordillo,Victor;Loring,Megan;Isaacson,KeithB;Griffith,LindaG
研究背景人类子宫内膜在性激素的作用下经历了生长、分化和破裂的周期性变化.上皮-基质间质通讯在乳腺癌介导的信号转导过程中的失调可能与治疗仍然不足的无数妇科疾病有关。在这里，我们描述了一个完全定义的，合成细胞外基质，能够以在模拟月经周期中捕获健康和疾病状态的方式共培养人子宫内膜上皮细胞和基质细胞。方法我们解析了周期依赖性子宫内膜整合素表达和基质组成，以定义候选细胞-基质相互作用线索，以包含在与基质金属蛋白酶交联的聚乙二醇（PEG）基水凝胶中-不稳定肽我们半经验性地筛选了代表子宫内膜的生物物理和分子特征的参数空间，以定义适合于上皮类器官、基质细胞、发现每种细胞类型都表现出特征性的形态和分子反应，当两种细胞类型共培养时，包封在水凝胶中，该水凝胶被调节至与天然组织相似的硬度状态，并用胶原蛋白衍生的粘附肽（GFOGER）和纤连蛋白衍生的肽（PHSRN-K-RGD）功能化。白细胞介素1B（IL 1B）诱导的炎症过程中细胞-细胞串扰的分析揭示了基质细胞介导的上皮细胞增殖的失调。ConclusionsAltogether，我们证明了一个完全合成的基质的发展，以维持子宫内膜微环境的动态变化，并支持其应用于了解月经健康和子宫内膜疾病。Manton基金会和NIH U 01（EB 029132）。
BackgroundThe human endometrium undergoes recurring cycles of growth, differentiation, and breakdown in response to sex hormones. Dysregulation of epithelial-stromal communication during hormone-mediated signaling may be linked to myriad gynecological disorders for which treatments remain inadequate. Here, we describe a completely defined, synthetic extracellular matrix that enables co-culture of human endometrial epithelial and stromal cells in a manner that captures healthy and disease states across a simulated menstrual cycle.MethodsWe parsed cycle-dependent endometrial integrin expression and matrix composition to define candidate cell-matrix interaction cues for inclusion in a polyethylene glycol (PEG)-based hydrogel crosslinked with matrix metalloproteinase-labile peptides. We semi-empirically screened a parameter space of biophysical and molecular features representative of the endometrium to define compositions suitable for hormone-driven expansion and differentiation of epithelial organoids, stromal cells, and co-cultures of the two cell types.FindingsEach cell type exhibited characteristic morphological and molecular responses to hormone changes when co-encapsulated in hydrogels tuned to a stiffness regime similar to the native tissue and functionalized with a collagen-derived adhesion peptide (GFOGER) and a fibronectin-derived peptide (PHSRN-K-RGD). Analysis of cell-cell crosstalk during interleukin 1B (IL1B)-induced inflammation revealed dysregulation of epithelial proliferation mediated by stromal cells.ConclusionsAltogether, we demonstrate the development of a fully synthetic matrix to sustain the dynamic changes of the endometrial microenvironment and support its applications to understand menstrual health and endometriotic diseases.FundingThis work was supported by The John and Karine Begg Foundation, the Manton Foundation, and NIH U01 (EB029132).