Replicating Dynamic Immune Responses at Single-Cell Resolution Within a Microfluidic Human Skin Equivalent

To enable in vitro investigation of human skin immunology, this study develops a microfluidic human skin equivalent (HSE) that supports the delivery of circulating immune cells via a vascular microchannel embedded within the dermis of a full-thickness construct. Within this platform, activation of keratinocyte inflammation promotes monocyte migration out of the vascular channel and into the dermal and epidermal compartments. Single-cell transcriptomic analysis reveals dynamic and cell-specific patterns of gene expression that are characteristic of acute activation and resolution of an inflammatory immune response, and the gene signatures of the monocyte-derived cells closely matches the differentiation trajectory of the monocytes into mature dermal macrophages. The microfluidic HSE is also applied to modeling age-associated immune dysfunction and accurately replicates elevated monocyte recruitment in aged skin. Thus, the microfluidic HSE presented here replicates key aspects of dynamic inflammatory immune responses and represents a tractable experimental tool for interrogating mechanisms of human skin immunology.