Autor: |
Lu S; Division of Renal Diseases and Hypertension, Department of Medicine, and., Jolly AJ; Division of Renal Diseases and Hypertension, Department of Medicine, and., Strand KA; Division of Renal Diseases and Hypertension, Department of Medicine, and., Dubner AM; Division of Renal Diseases and Hypertension, Department of Medicine, and., Mutryn MF; Division of Renal Diseases and Hypertension, Department of Medicine, and., Moulton KS; Division of Cardiology, Department of Medicine, and., Nemenoff RA; Division of Renal Diseases and Hypertension, Department of Medicine, and.; Consortium for Fibrosis Research and Translation, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Majesky MW; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.; Department of Pediatrics and Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA., Weiser-Evans MC; Division of Renal Diseases and Hypertension, Department of Medicine, and.; Consortium for Fibrosis Research and Translation, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Cardio Vascular Pulmonary Research Lab, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. |
Abstrakt: |
Resident vascular adventitial SCA1+ progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage-tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA-sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling were significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM-specific expression of GLI-Kruppel family member GLI1 (Gli1), we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell-specific Kruppel-like factor 4 (Klf4) depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a profibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable antifibrotic approach. |