Decoding microbe-epithelial stem cell interactions in health and disease

总结 哺乳动物已经与栖息在我们周围的微生物形成了一个进化联盟。 上皮边界这种终生的关系是在出生时就建立起来的，当时微生物第一次在我们的 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 在西方世界，影响约20%儿童的皮肤病，其根源在于表皮屏障 功能障碍和肠道生态失调。然而，令人惊讶的是，人们对功能性 新生儿皮肤中定植细胞和上皮细胞之间的相互作用。 表皮干细胞和祖细胞（ESPCs）在我们的一生中维持表皮， 从微环境或“利基”中获取线索。我们最近发现了一种非凡的能力 让ESPC感知、响应和记忆炎症刺激。是否以及如何 表皮信号同样影响ESPCs和形状表皮组织适合性是一个开放的 问题 在这里，我们解决了一个诱人的可能性，即浮游微生物是迄今为止 不受重视的ESPC利基组件。因此，我们的目的是阐明他们的作用，指导ESPC 分化、先天免疫激活以及因此上皮屏障功能和适应性 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 生命早期上皮-微生物对话影响特应性疾病易感性。我们的建议用途 遗传上易处理的真菌菌株和表皮特异性缺失的确定的微生物 具有最先进的体内组织特异性基因调节系统的传感器， 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， 从这些研究中产生的结果将为开发基于微生物群的疗法奠定基础 来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.