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| Status |
Public on Feb 22, 2021 |
| Title |
The fibrous cap of atherosclerotic lesions arise from multiple cellular origins by PDGFRB- and bioenergetic mechanisms |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Stable atherosclerotic plaques are characterized by a thick extracellular matrix (ECM)-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMC). Herein, we show that in murine and human lesions, ~20-40% of ACTA2+ fibrous caps cells, respectively, are derived from non-SMC sources, including endothelial cells (EC) or macrophages that have undergone Endothelial-to-Mesenchymal (EndoMT) or Macrophage-to-Mesenchymal (MMT) transitions. In addition, weshow that SMC-specific knockout of the platelet-derived growth factor receptor beta (PDGFRB) in Apoe-/- mice fed a Western diet (WD) for 18 weeks results in brachiocephalic artery (BCA) lesions nearly devoid of SMC. While absence of SMCs does not affect lesion size, remodeling, or ACTA2+ fibrous cap cell content, prolonged WD feeding results in reduced indices of stability, indicating that EndoMT and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using RNA-seq analysis of the BCA region and in vitro models, we demonstrate that SMC to MF transitions (SMC-MFT) is induced by PDGF and TFGβ and is dependent on aerobic glycolysis, while EndoMT is induced by IL1β and TGFβ. Together, we provide the first quantitative evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF state through distinct signaling pathways that are either dependent on or associated with extensive metabolic reprogramming.
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| Overall design |
scRNA-seq of atherosclerotic plaques of Apoe-/- mouse (with or without specific SMC KO of PDGFRB)
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| Contributor(s) |
Newman AA, Serbulea V, Bailys RA, Shankman LS, Bradley X, Alencar GF, Owsiany K, Deaton RA, Karnewar S, Shomsuzzaman S, Salamon A, Reddy MS, Guo L, Finn A, Virmani R, Cherepanova OA, Owens GK |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Dec 18, 2020 |
| Last update date |
Feb 24, 2021 |
| Contact name |
Gary K Owens |
| Organization name |
University of Virginia
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| Street address |
415 Lane Road MR5 Building Room 1322
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| City |
Charlottesville |
| State/province |
VA |
| ZIP/Postal code |
22908 |
| Country |
USA |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA686420 |
| SRA |
SRP298495 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE163519_RAW.tar |
123.3 Mb |
(http)(custom) |
TAR (of TAR) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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