Developing in situ transcriptomics of a bioprinted follicular skin model

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PROJECT SUMMARY / ABSTRACT The goal of this proposal is to develop a platform to model host-microbe interactions in skin, featuring a 3D bioprinted follicular skin model and spatial transcriptomics of host and microbial cells to retain physiologically relevant interactions. In human skin, a majority of microbial interactions with the host epithelium and cutaneous immunity is thought to occur in deeper, protective adnexal structures, e.g., hair follicles and glands. For example, recent work in mice has suggested a homeostatic interaction between different tissue resident cells, sebaceous glands, and the microbiome. Given the substantial diversity of the microbiome – encompassing hundreds of different bacterial and fungal species, it would be highly impactful to model such potential interactions systematically. In addition, examining interactions with human cells would best provide translational data on cellular response to microbial colonization. However, there are major limitations in the 3D skin models that are available – they lack complex structures where skin microbes reside, and second, current approaches to investigate host-microbiome interactions lack resolution on spatial activity. Here, our two aims address these key limitations. In Aim 1, we will develop a 3D bioprinted skin tissue model containing follicular structures. In Aim 2, we will develop in situ microbial sequencing technology for spatial profiling of microbial colonization of these tissues and other available human 3D skin models. These aims taken together will allow us to address fundamental questions on the underlying biology of the skin microbiome, which we will pilot in this R21. Our success would result in two new technologies that would enable construction of a high-resolution spatial map of the microbiome and host interactions, enabling foundational investigations into mechanisms of interstrain interactions and regulation of virulence to promote skin homeostasis.