Lineage tracing of cells involved in atherosclerosis.
Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis. We here aim to identify the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions.



We combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis.



We found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68(+) cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2, p = 0.02), and vascular cell adhesion molecule (Vcam1, p = 0.05), as well as increased mRNA levels of genes related to matrix synthesis such as Col1a2 (p = 0.01) and Fn1 (p = 0.04), than non SM-derived CD68(+) cells.



These results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression.
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. Electronic address: julian.albarran@mpi-bn.mpg.de.
Julián
J
Albarrán-Juárez
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Harmandeep
H
Kaur
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Myriam
M
Grimm
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Medical Faculty, Goethe University Frankfurt, Germany.
Stefan
S
Offermanns
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Medical Faculty, Goethe University Frankfurt, Germany.
Nina
N
Wettschureck
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D050197:Atherosclerosis / Q000503:physiopathology*; D019070:Cell Lineage; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010641:Phenotype; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C081026:CD68 protein, mouse; D000097382:CD68 Molecule
Atherosclerosis; Gene expression; Lineage tracing; Macrophage; Smooth muscle cell; Transdifferentiation