Minnesota Tissue Mapping Center for Senescent Cells

Project Summary Senescent cells (SnCs) are known to play a causal role in aging and numerous age-related diseases. However, they also contribute to wound healing and tissue remodeling. Both physiological and pathological roles are linked to the secretome of SnCs and their complex interaction with the immune system, which is thought to play an important role in clearing SnCs. Most of what we have learned about SnCs is derived from mice where it has been clearly demonstrated that genetic or pharmacologic removal of SnCs in aged or diseased organisms reduces frailty; improves strength, endurance, and resilience; and attenuates a variety of age-related diseases including Alzheimer’s. This novel approach of therapeutically targeting a fundamental aging process common to many diseases – rather than drugging disease-specific perturbations (e.g., low insulin or hypertension) – could have a tremendous impact on our aging population. However, much needs to be learned about SnCs in humans to deploy such approaches safely and effectively. This project aims to establish a Tissue Mapping Center at the University of Minnesota (MN TMC) to contribute to the SenNet Consortium, which intends to build a 4D atlas of SnCs in multiple human organs with healthy aging. MN TMC proposes to focus on adipose (omental and subcutaneous), skeletal muscle (Vastus lateralis), liver, and ovarian tissue. This selection is based on MN TMC’s expertise in the biology, cell biology, and immunology of these organs; in studying SnCs in these organs; and experience with single cell technologies in these organs. The MN TMC and its Administrative Core will be led by PIs with complementary expertise in SnCs and computational biology/health informatics. The Biospecimen Core will be led by the UMN Chairman of Surgery and an accomplished pathologist. The Biological Analysis Core will be led by an expert in SnC and a molecular pathologist leading spatial genomics at UMN. The Data Analysis Core will be led by three bioinformaticians with expertise in modeling, single cell, and spatial-omics analysis, and blending patient electronic health records with -omics data. A unique feature of the proposed MN TMC is that the entire workflow will be housed within existing infrastructure/cores: from CTSI and BioNet, which manage human subjects research, tissue procurement, annotation, and distribution/storage, to the genomic/ proteomics/imaging cores, along with the Institute of Health Informatics for data management and multiplexing. Key personnel include leadership of all of these UMN components. This approach provides unequaled stability of our analytical pipeline and in-place quality control and assurance mechanisms. A second unique feature of the proposed MN TMC is our ability to perform spatial transcriptomics and proteomics on formalin-fixed paraffin embedded biospecimens, which enables analysis of the most stable biospecimens and virtually any archived material. Overall, the goal of the MN TMC is to make a significant contribution to the 4D atlas of human SnCs, working closely with NIH and other TMCs to develop and adhere to standards created by the SenNet Consortium.