Senescence-on-a-chip: Building a microphysiological 3D skin model

Aging is an increasingly emergent public health issue, in large part because it is accompanied by a higher frequency of chronic age-related diseases. Aging occurs naturally as a consequence of time (upon repeated cellular replication) and is influenced by a number of environmental factors. Human skin, like all other tissues, undergoes an intrinsic aging process during an individual’s lifespan known as chronological aging. Additionally, the skin is constantly exposed to environmental factors such as UV radiation (UVR), which is recognized as the major risk factor for the development of many skin cancers and accelerated skin aging, known as photoaging, which is associated with hyperpigmentation and accelerated melanoma formation. In the skin, there is an age- associated accumulation of senescent melanocytes, keratinocytes and fibroblasts capable of expressing the senescence-associated secretory phenotype (SASP), which promotes inflammation through a complex network of auto- and paracrine reinforcement that modifies the tissue microenvironment and has a profound deleterious effect on skin structure and integrity. Thus, it is necessary to determine the characteristics of the major skin- resident cell types undergoing senescence, as well as their individual SASP profiles expressed during chronological and extrinsically-induced aging that play a role in the establishment of a skin microenvironment conducive to age-related disorders. Our lab has developed sophisticated 3D skin models that recapitulate normal skin physiology within a microfluidic platform in vitro, which can combined with other organs in a modular tissue-on-a-chip platform. 3D engineered tissues cultured in microfluidic platforms are powerful tools to recapitulate physiological conditions and investigate physiological phenomena in a controlled environment. We will generate 3D skin models that encompass critical biological variables for mapping senescent cells in tissues, and will encompass: 1) both sexes; 2) the full range of skin pigmentation phototypes; and 3) age ranges across the human lifespan. Our skin microfluidic platform, combined with innovative techniques such as spatial transcriptomics, represents a powerful new tool to investigate the mechanisms leading to senescence in the skin and new approaches to revert age-related conditions. This proposal will have immediate and seamless integration into the recently established CUSTMAP Center at Columbia University, which is one of the founding Tissue Mapping Centers of the SenNet consortium. Microfluidic tissue models can be customized for many of the tissues represented across the SenNet, enabling the generation of a wide range of senescence-on-a-chip platforms for the Consortium.