Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

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Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs. / Jacobsen, Kevin; Lund, Marie Bek; Shim, Jeong; Gunnersen, Stine; Füchtbauer, Ernst-Martin; Kjolby, Mads; Carramolino, Laura; Bentzon, Jacob Fog.

In: JCI Insight, Vol. 2, No. 19, e95890, 05.10.2017.

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@article{e49e459e2180481881a1a2abf7946cd4,
title = "Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs",
abstract = "Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP+Apoe-/- and Apoe-/- mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP+ or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2+ SMCs in the cap and heterogeneous ACTA2- SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.",
keywords = "ACTIVATION, ARTERIAL-WALL, ATHEROGENESIS, CONTRIBUTES, INDUCTION, MACROPHAGE-LIKE CELLS, MICE, PHENOTYPE, SENESCENCE, SMOOTH-MUSCLE-CELLS",
author = "Kevin Jacobsen and Lund, {Marie Bek} and Jeong Shim and Stine Gunnersen and Ernst-Martin F{\"u}chtbauer and Mads Kjolby and Laura Carramolino and Bentzon, {Jacob Fog}",
year = "2017",
month = "10",
day = "5",
doi = "10.1172/jci.insight.95890",
language = "English",
volume = "2",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "19",

}

RIS

TY - JOUR

T1 - Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

AU - Jacobsen, Kevin

AU - Lund, Marie Bek

AU - Shim, Jeong

AU - Gunnersen, Stine

AU - Füchtbauer, Ernst-Martin

AU - Kjolby, Mads

AU - Carramolino, Laura

AU - Bentzon, Jacob Fog

PY - 2017/10/5

Y1 - 2017/10/5

N2 - Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP+Apoe-/- and Apoe-/- mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP+ or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2+ SMCs in the cap and heterogeneous ACTA2- SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.

AB - Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP+Apoe-/- and Apoe-/- mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP+ or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2+ SMCs in the cap and heterogeneous ACTA2- SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.

KW - ACTIVATION

KW - ARTERIAL-WALL

KW - ATHEROGENESIS

KW - CONTRIBUTES

KW - INDUCTION

KW - MACROPHAGE-LIKE CELLS

KW - MICE

KW - PHENOTYPE

KW - SENESCENCE

KW - SMOOTH-MUSCLE-CELLS

U2 - 10.1172/jci.insight.95890

DO - 10.1172/jci.insight.95890

M3 - Journal article

VL - 2

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 19

M1 - e95890

ER -