Decoding microbe-epithelial stem cell interactions in health and disease

摘要 哺乳动物与栖息在地球上的共生微生物形成了进化联盟 上皮界。这种终生的关系是在微生物第一次殖民我们的时候就建立起来的 表面。新生儿微生物群落的改变与几种流行的 上皮炎性疾病，包括特应性皮炎。特应性皮炎是一种毁灭性的 皮肤病影响西方世界约20%的儿童，根源于表皮屏障 功能障碍和共生失调。然而，令人惊讶的是，人们对功能性的 新生儿皮肤中定植共生体和上皮细胞群之间的相互作用。 表皮干细胞和祖细胞(ESPC)通过以下方式在我们的一生中维持表皮 从微环境或“利基”中寻找线索。我们最近发现了一种非凡的能力 使EPC能够感知、响应和记忆炎症刺激。是否以及如何 共生信号同样影响ESPC和形状表皮组织的适合性是一个开放的 问题。 在这里，我们讨论了一种诱人的可能性，即共生微生物是迄今为止 不受欢迎的ESPC利基组件。因此，我们的目标是阐明他们在指导ESPC方面的作用 分化，先天免疫激活，因此，上皮屏障功能和适合性 在新生儿中，当微生物第一次在皮肤上定居时。我们还试图从功能上研究如何 生命早期上皮-微生物对话影响特应性疾病的易感性。我们建议的用途 基因上易处理的共生菌株和定义的微生物的表皮特异性缺失 传感器采用最先进的体内组织特异性基因调制系统来系统 同时操纵宿主和微生物允许全面和机械地理解 微生物-ESPC对话及其对表皮健康和疾病的影响。调查结果显示 这些研究产生的数据将为开发基于微生物群的疗法奠定基础 增强表皮屏障，减轻特应性疾病。

Summary Mammals have formed an evolutionary alliance with the commensal microbes that inhabit our epithelial boundaries. This lifelong relationship is forged at birth when microbes first colonize our surfaces. Alterations in neonatal microbial communities are associated with several prevalent epithelial inflammatory diseases, including atopic dermatitis. Atopic dermatitis is a devastating skin disease affecting about 20% of children in the western world and is rooted in epidermal barrier dysfunction and commensal dysbiosis. Yet, surprisingly little is known about the functional interactions between colonizing commensals and epithelial populations in neonatal skin. Epidermal stem and progenitor cells (ESPCs) maintain the epidermis throughout our lifetime by taking cues from the microenvironment or “niche”. We recently uncovered a remarkable capacity for ESPCs to sense, respond to, and remember inflammatory stimuli. Whether and how commensal signals similarly influence ESPCs and shape epidermal tissue fitness is an open question. Here we address the tantalizing possibility that commensal microbes are a heretofore unappreciated ESPC niche component. Thus, we aim to illuminate their roles in directing ESPC differentiation, innate immune activation and, consequently, epithelial barrier function and fitness in neonates, when microbes first colonize the skin. We also seek to functionally examine how the early-in-life epithelial–microbe dialogue impacts atopic disease susceptibility. Our proposed use of genetically tractable commensal strains and epidermal-specific deletion of defined microbial sensors with a state-of-the art in vivo tissue-specific gene modulation system to systematically manipulate both host and microbe allows for a comprehensive and mechanistic understanding of the microbe–ESPC dialogue and its impact on epidermal health and disease. The findings the generated from these studies will lay the groundwork for developing microbiota-based therapies to boost the epidermal barrier and mitigate atopic disease.