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Mesenchymal-endothelial transition contributes to cardiac neovascularization.

Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F, Lu Y, Stanbouly S, Huang J, Rojas M, Vondriska TM, Stefani E, Deb A - Nature (2014)

Bottom Line: We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate.Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function.These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology &Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

ABSTRACT
Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

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MEndoT in FSP1Cre:R26RtdTomato miceFSP1Cre:R26RtdTomato mice were subjected to (a) sham or (b) ischemia-reperfusion cardiac injury. Hearts were harvested 3 days after injury and stained for endothelial marker VECAD or isolectin. Injury region demonstrated tdTomato labeled cells expressing VECAD or isolectin (arrowheads, n=4). Scale bar: 10μm. (c) Quantitation of labeled fibroblasts that express VECAD or isolectin in sham injured animals and in the injury border zone (mean±S.E.M., *p<0.01, n=4)
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Figure 10: MEndoT in FSP1Cre:R26RtdTomato miceFSP1Cre:R26RtdTomato mice were subjected to (a) sham or (b) ischemia-reperfusion cardiac injury. Hearts were harvested 3 days after injury and stained for endothelial marker VECAD or isolectin. Injury region demonstrated tdTomato labeled cells expressing VECAD or isolectin (arrowheads, n=4). Scale bar: 10μm. (c) Quantitation of labeled fibroblasts that express VECAD or isolectin in sham injured animals and in the injury border zone (mean±S.E.M., *p<0.01, n=4)

Mentions: Finally, we subjected FSP1Cre:R26RtdTomato mice to ischemic cardiac injury to confirm MEndoT with another Cre driver. The FSP1Cre has been used to track cardiac fibroblast after in vivo reprogramming8,9. By day 3 post injury, 31±4% and 23±5% of tdTomato labeled cells in the injury region expressed the endothelial markers isolectin and VECAD compared to 2±1% and 4±1% in sham injured animals (Extended Data Fig. 6a–c) confirming MEndoT observations made using the Col1a2CreERT driver.


Mesenchymal-endothelial transition contributes to cardiac neovascularization.

Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F, Lu Y, Stanbouly S, Huang J, Rojas M, Vondriska TM, Stefani E, Deb A - Nature (2014)

MEndoT in FSP1Cre:R26RtdTomato miceFSP1Cre:R26RtdTomato mice were subjected to (a) sham or (b) ischemia-reperfusion cardiac injury. Hearts were harvested 3 days after injury and stained for endothelial marker VECAD or isolectin. Injury region demonstrated tdTomato labeled cells expressing VECAD or isolectin (arrowheads, n=4). Scale bar: 10μm. (c) Quantitation of labeled fibroblasts that express VECAD or isolectin in sham injured animals and in the injury border zone (mean±S.E.M., *p<0.01, n=4)
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Related In: Results  -  Collection

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Figure 10: MEndoT in FSP1Cre:R26RtdTomato miceFSP1Cre:R26RtdTomato mice were subjected to (a) sham or (b) ischemia-reperfusion cardiac injury. Hearts were harvested 3 days after injury and stained for endothelial marker VECAD or isolectin. Injury region demonstrated tdTomato labeled cells expressing VECAD or isolectin (arrowheads, n=4). Scale bar: 10μm. (c) Quantitation of labeled fibroblasts that express VECAD or isolectin in sham injured animals and in the injury border zone (mean±S.E.M., *p<0.01, n=4)
Mentions: Finally, we subjected FSP1Cre:R26RtdTomato mice to ischemic cardiac injury to confirm MEndoT with another Cre driver. The FSP1Cre has been used to track cardiac fibroblast after in vivo reprogramming8,9. By day 3 post injury, 31±4% and 23±5% of tdTomato labeled cells in the injury region expressed the endothelial markers isolectin and VECAD compared to 2±1% and 4±1% in sham injured animals (Extended Data Fig. 6a–c) confirming MEndoT observations made using the Col1a2CreERT driver.

Bottom Line: We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate.Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function.These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology &Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

ABSTRACT
Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

Show MeSH
Related in: MedlinePlus