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

项目总结 老龄化是一个日益突出的公共卫生问题，在很大程度上是因为它伴随着更高的 与年龄有关的慢性疾病的发生频率。衰老是自然发生的，是时间的结果(反复 细胞复制)，并受许多环境因素的影响。人类皮肤，就像所有其他组织一样， 在一个人的一生中经历一个内在的衰老过程，称为时序衰老。另外， 皮肤经常暴露在环境因素中，如紫外线辐射(UVR)，这是公认的 导致许多皮肤癌和加速皮肤老化的主要风险因素，即所谓的光老化， 这与色素沉着和加速黑色素瘤的形成有关。在皮肤里，有一个年龄- 衰老的黑素细胞、角质形成细胞和成纤维细胞能够表达 衰老相关分泌表型(SASP)，通过复杂的网络促进炎症 自体和旁分泌强化，改变组织微环境，具有深远的危害 对皮肤结构和完整性的影响。因此，有必要确定主要皮肤的特征- 经历衰老的驻留细胞类型及其各自的SASP谱在 在建立皮肤微环境中起作用的时序和外在诱导的衰老 有利于与年龄相关的疾病。我们的实验室已经开发出复杂的3D皮肤模型，可以概括 体外微流控平台内的正常皮肤生理，可与其他器官组合成模块 芯片上组织平台。在微流控平台上培养的3D工程组织是治疗 总结生理条件，研究受控环境中的生理现象。我们 将生成3D皮肤模型，其中包含绘制组织中衰老细胞的关键生物变量， 它将涵盖：1)男女；2)全系列皮肤色素沉着照片类型；3)不同年龄段的 人类的寿命。我们的皮肤微流控平台，结合空间等创新技术 转录学是研究皮肤衰老机制的有力新工具。 以及恢复与年龄相关的疾病的新方法。这项建议将立即和无缝地 整合到哥伦比亚大学最近成立的CUSTMAP中心，该中心是创始机构之一 Sennet财团的组织地图绘制中心。微流控组织模型可以为许多 整个Sennet上的组织代表，使广泛的芯片上衰老的产生成为可能 财团的平台。

PROJECT SUMMARY 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 genders; 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.