Abstract 4361334: The company you keep: Cell-Cell Interactions Defined by 9p21 Risk Loci Change Interaction of iPSC derived VSMCs with Fibromyocytes

Abstract

Introduction: Coronary artery disease (CAD) involves complex crosstalk of various cell types in the vasculature, key among them being vascular smooth muscle cells (VSMCs). Additionally, genome wide association studies have identified several gene loci that are strongly associated with CAD, though many of these do not have defined mechanisms for conveying this risk. Induced pluripotent stem cells (iPSCs) have become a critical tool in elucidating the mechanistic underpinning of genomic risk. Methods: We studied the differences in iPSCs-derived VSMCs (iVSMCs) from risk (RR) and non-risk (NN) haplotypes of 9p21 and computationally evaluated the cell-cell interactions from scRNAseq derived transcriptomic profiling compared to cells from coronary arteries with atherosclerosis or not. Using Seruat and Cellchat packages in R, we evaluated scRNAseq data of cell types and then incoming and outgoing interactions between cells. We integrated our iVSMC data to better define changes in iVSMCs to the mature VSMCs. Results: Overall cell distribution was consistent between iVSMCs and the VSMC clusters. Additionally, analysis was completed of the possible cell clusters as influenced by iVSMC integration. In the setting of atherosclerotic arteries, incoming and outgoing signaling to fibromyocytes saw a dynamic change. There was virtually no signaling. Comparatively, there was significantly higher signaling present in the non-atherosclerotic arteries for fibromyoctes. To understand if iVSMCs were involved in this change, we filtered all signaling in atherosclerotic coronary arteries and observed that in the top 10% of cell-cell communications between iVSMCs would be to VSMCs and macrophages. In comparison, the top 10% of cell-cell communication in non-atherosclerotic coronary arteries and iVSMCs was to fibromyocytes and SMCs. Upon evaluation of the differential gene expression driving these differences expression of SPP1 and other markers of extracellular matrix regulation. Conclusion: In conclusion, lack of fibromyocyte cells and iVSMC to fibromyoctye cell signaling may give insights into the lack of stabilization of atherosclerotic lesion in 9p21 risk haplotype individuals. Understanding the dynamics between these cells could provide insights for novel therapy for mitigation of risk from loci.