There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervix, limiting development of new therapies for treating infertility, infection or cancer. We developed three microphysiologic human ectocervix models to study hormone action during homeostasis. First, we reconstructed ectocervix using decellularized extracellular matrix scaffolds, which supported cell integration and could be clinically useful. Secondly, we generated organotypic systems consisting of ectocervical explants co-cultured with murine ovaries or cycling exogenous hormones, which mimicked human menstrual cycles. Finally, we engineered ectocervix tissue consisting of tissue-specific stromal-equivalents and fully-differentiated epithelium that mimicked in vivo physiology, including squamous maturation, hormone response, and mucin production, and remained viable for 28 days in vitro. The localization of differentiation-dependent mucins in native and engineered tissue was identified for the first time, which will allow increased efficiency in mucin-targeting for drug delivery. In summary, we developed and characterized three microphysiologic human ectocervical tissue models that will be useful for a variety of research applications, including preventative and therapeutic treatments, drug and toxicology studies, and fundamental research on hormone action in a historically understudied tissue that is critical for women's health.

中文翻译：

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开发具有生理内分泌和旁分泌信号的人类宫颈外组织模型†。

缺乏充分代表人类外宫颈独特粘膜环境的研究模型，限制了治疗不孕症、感染或癌症的新疗法的开发。我们开发了三种微生理人类子宫颈模型来研究体内平衡过程中的激素作用。首先，我们使用脱细胞的细胞外基质支架重建了子宫颈，这支持细胞整合并且在临床上可能有用。其次，我们生成了器官型系统，该系统由与小鼠卵巢或循环外源激素共培养的宫颈外植体组成，模拟人类月经周期。最后，我们设计了由组织特异性基质等价物和完全分化的上皮组成的外宫颈组织，模拟了体内生理学，包括鳞状成熟、激素反应、和粘蛋白的产生，并在体外保持活力 28 天。首次确定了分化依赖性粘蛋白在天然和工程组织中的定位，这将提高药物递送的粘蛋白靶向效率。总之，我们开发并表征了三种微生理人类宫颈外膜组织模型，这些模型将用于各种研究应用，包括预防性和治疗性治疗、药物和毒理学研究，以及对历史上未被充分研究的组织中激素作用的基础研究，这对于女性健康。这将提高药物递送的粘蛋白靶向效率。总之，我们开发并表征了三种微生理人类宫颈外膜组织模型，这些模型将用于各种研究应用，包括预防性和治疗性治疗、药物和毒理学研究，以及对历史上未被充分研究的组织中激素作用的基础研究，这对于女性健康。这将提高药物递送的粘蛋白靶向效率。总之，我们开发并表征了三种微生理人类宫颈外膜组织模型，这些模型将用于各种研究应用，包括预防性和治疗性治疗、药物和毒理学研究，以及对历史上未被充分研究的组织中激素作用的基础研究，这对于女性健康。