Smooth Muscle Cell Phenotypic Diversity At the Crossroads of Lineage Tracing and Single-Cell Transcriptomics

Vascular smooth muscle cells (SMC) play a critical role in controlling blood pressure and blood distribution, as well as maintaining the structural integrity of the blood vessel. SMC also participate in physiological and pathological vascular remodeling due to their remarkable ability to dynamically modulate their phenotype. During the past decade, the development of in vivo fate mapping systems for unbiased identification and tracking of SMC and their progeny has led to major discoveries as well as the reevaluation of well-established concepts about the contribution of vascular SMC in major vascular diseases including atherosclerosis. Lineage tracing studies revealed that SMC undergoes multiple phenotypic transitions characterized by the expression of markers of alternative cell types (eg, macrophage-like and mesenchymal-stem cell-like) and populate injured or diseased vessels by oligoclonal expansion of a limited number of medial SMC. With the development of high-throughput transcriptomics and single-cell RNA sequencing (scRNAseq), the field is moving forward towards in-depth SMC phenotypic characterization. Herein, we review the major observations put forth by lineage and clonality tracing studies and the evidence in support for SMC phenotypic diversity in healthy and diseased vascular tissue. We will also discuss the opportunities and remaining challenges of combining lineage tracing and single-cell transcriptomics technologies, as well as studying the functional relevance of SMC phenotypic transitions and identifying the mechanisms controlling them.