Abstract P178: A Novel Subset Of Adventitial Vascular Stem Cells Paracrine Control Media Smooth Muscle Cell Dedifferentiation Leading To Intimal Hyperplasia In Vein Grafts

Abstract

Vein graft failure (VGF) is associated with vein graft (VG) intimal hyperplasia, which is characterized by abnormal accumulation of vascular smooth muscle cells (SMCs). The majority of neointimal SMCs are derived from pre-existing vascular SMCs via a process of vascular SMC dedifferentiation; however, the underlying mechanisms remain poorly understood. Here, we tracked down the fate of vascular stem cells (VSCs) expressing stem cell antigen 1 (SCA1) in VG remodeling. After transplantation, most of the donor venous cells including endothelial cells, SMCs, and VSCs died within 3 days, and the recipient arterial SCA1+ VSCs were recruited to repopulate the adventitia and the intima but did not differentiate into neointimal SMCs in VGs. However, ablation of the SCA1+ VSCs ameliorated intimal hyperplasia in VGs. Single-Cell RNA sequencing (scRNA-seq) analysis revealed a unique subset of VSCs expressing Sca1 and cyclin-dependent kinase 8 (Cdk8) in the artery. Notably, the number of SCA1+CDK8+ cells was increased in the adventitia prior to dramatic proliferation of SMCs in the media and neointima in VGs. Inactivation of CDK8 intensified SCA1+ VSC naïve stemness but suppressed SCA1+ VSC proliferation, migration, and exosome release for paracrine enforcement of vascular SMC dedifferentiation. A short-time perivascular delivery of CDK8 inhibitors ameliorated adventitial SCA1+ VSC accumulation associated with a long-term efficacy in suppressing intimal hyperplasia in VGs. There findings uncover that a novel subset of adventitial VSCs paracrine control media SMC dedifferentiation for intimal hyperplasia in VGs toward VGF.