Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage

Research output: Contribution to journalArticle

BACKGROUND: We have previously shown that activation of cell-autonomous innate immune signaling facilitates the transdifferentiation of fibroblasts into induced endothelial cells, and is required to generate induced endothelial cells with high fidelity for endothelial lineage. Recent studies indicate that a glycolytic switch plays a role in induced pluripotent stem cell generation from somatic cells. METHODS: Seahorse and metabolomics flux assays were used to measure the metabolic changes during transdifferentiation in vitro, and Matrigel plug assay was used to assess the effects of glycolysis modulators on transdifferentiation in vivo. RESULTS: The metabolic switch begins rapidly after activation of innate immunity, before the expression of markers of endothelial lineage. Inhibiting glycolysis impaired, whereas facilitating glycolysis enhanced, the generation of induced endothelial cells. The toll-like receptor 3 agonist poly I:C increased expression of the mitochondrial citrate transporter Slc25A1, and the nuclear ATP-citrate lyase, in association with intracellular accumulation of citrate, the precursor for acetyl coenzyme A. These metabolic changes were coordinated with increased histone acetylation during transdifferentiation. CONCLUSION: Innate immune signaling promotes a glycolytic switch that is required for transdifferentiation, both processes being attenuated by ATP-citrate lyase knockdown. These data shed light on a novel link between metabolism and epigenetic modulation in transdifferentiation.

Original languageEnglish (US)
Pages (from-to)119-133
Number of pages15
JournalCirculation
Volume139
Issue number1
Early online dateSep 28 2018
DOIs
StatePublished - Jan 2 2019

PMID: 30586707

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Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage. / Lai, Li; Reineke, Erin L.; Hamilton, Dale J.; Cooke, John P.

In: Circulation, Vol. 139, No. 1, 02.01.2019, p. 119-133.

Research output: Contribution to journalArticle

Harvard

Lai, L, Reineke, EL, Hamilton, DJ & Cooke, JP 2019, 'Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage' Circulation, vol. 139, no. 1, pp. 119-133. https://doi.org/10.1161/CIRCULATIONAHA.118.035741, https://doi.org/10.1161/CIRCULATIONAHA.118.035741

APA

Lai, L., Reineke, E. L., Hamilton, D. J., & Cooke, J. P. (2019). Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage. Circulation, 139(1), 119-133. https://doi.org/10.1161/CIRCULATIONAHA.118.035741, https://doi.org/10.1161/CIRCULATIONAHA.118.035741

Vancouver

Lai L, Reineke EL, Hamilton DJ, Cooke JP. Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage. Circulation. 2019 Jan 2;139(1):119-133. https://doi.org/10.1161/CIRCULATIONAHA.118.035741, https://doi.org/10.1161/CIRCULATIONAHA.118.035741

Author

Lai, Li ; Reineke, Erin L. ; Hamilton, Dale J. ; Cooke, John P. / Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage. In: Circulation. 2019 ; Vol. 139, No. 1. pp. 119-133.

BibTeX

@article{ca24b45c5b4f4dc79d8d282ff60f0fef,
title = "Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage",
abstract = "BACKGROUND: We have previously shown that activation of cell-autonomous innate immune signaling facilitates the transdifferentiation of fibroblasts into induced endothelial cells, and is required to generate induced endothelial cells with high fidelity for endothelial lineage. Recent studies indicate that a glycolytic switch plays a role in induced pluripotent stem cell generation from somatic cells. METHODS: Seahorse and metabolomics flux assays were used to measure the metabolic changes during transdifferentiation in vitro, and Matrigel plug assay was used to assess the effects of glycolysis modulators on transdifferentiation in vivo. RESULTS: The metabolic switch begins rapidly after activation of innate immunity, before the expression of markers of endothelial lineage. Inhibiting glycolysis impaired, whereas facilitating glycolysis enhanced, the generation of induced endothelial cells. The toll-like receptor 3 agonist poly I:C increased expression of the mitochondrial citrate transporter Slc25A1, and the nuclear ATP-citrate lyase, in association with intracellular accumulation of citrate, the precursor for acetyl coenzyme A. These metabolic changes were coordinated with increased histone acetylation during transdifferentiation. CONCLUSION: Innate immune signaling promotes a glycolytic switch that is required for transdifferentiation, both processes being attenuated by ATP-citrate lyase knockdown. These data shed light on a novel link between metabolism and epigenetic modulation in transdifferentiation.",
keywords = "cell transdifferentiation, endothelium, glycolysis, mitochondria",
author = "Li Lai and Reineke, {Erin L.} and Hamilton, {Dale J.} and Cooke, {John P.}",
year = "2019",
month = "1",
day = "2",
doi = "10.1161/CIRCULATIONAHA.118.035741",
language = "English (US)",
volume = "139",
pages = "119--133",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

RIS

TY - JOUR

T1 - Glycolytic Switch Is Required for Transdifferentiation to Endothelial Lineage

AU - Lai, Li

AU - Reineke, Erin L.

AU - Hamilton, Dale J.

AU - Cooke, John P.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - BACKGROUND: We have previously shown that activation of cell-autonomous innate immune signaling facilitates the transdifferentiation of fibroblasts into induced endothelial cells, and is required to generate induced endothelial cells with high fidelity for endothelial lineage. Recent studies indicate that a glycolytic switch plays a role in induced pluripotent stem cell generation from somatic cells. METHODS: Seahorse and metabolomics flux assays were used to measure the metabolic changes during transdifferentiation in vitro, and Matrigel plug assay was used to assess the effects of glycolysis modulators on transdifferentiation in vivo. RESULTS: The metabolic switch begins rapidly after activation of innate immunity, before the expression of markers of endothelial lineage. Inhibiting glycolysis impaired, whereas facilitating glycolysis enhanced, the generation of induced endothelial cells. The toll-like receptor 3 agonist poly I:C increased expression of the mitochondrial citrate transporter Slc25A1, and the nuclear ATP-citrate lyase, in association with intracellular accumulation of citrate, the precursor for acetyl coenzyme A. These metabolic changes were coordinated with increased histone acetylation during transdifferentiation. CONCLUSION: Innate immune signaling promotes a glycolytic switch that is required for transdifferentiation, both processes being attenuated by ATP-citrate lyase knockdown. These data shed light on a novel link between metabolism and epigenetic modulation in transdifferentiation.

AB - BACKGROUND: We have previously shown that activation of cell-autonomous innate immune signaling facilitates the transdifferentiation of fibroblasts into induced endothelial cells, and is required to generate induced endothelial cells with high fidelity for endothelial lineage. Recent studies indicate that a glycolytic switch plays a role in induced pluripotent stem cell generation from somatic cells. METHODS: Seahorse and metabolomics flux assays were used to measure the metabolic changes during transdifferentiation in vitro, and Matrigel plug assay was used to assess the effects of glycolysis modulators on transdifferentiation in vivo. RESULTS: The metabolic switch begins rapidly after activation of innate immunity, before the expression of markers of endothelial lineage. Inhibiting glycolysis impaired, whereas facilitating glycolysis enhanced, the generation of induced endothelial cells. The toll-like receptor 3 agonist poly I:C increased expression of the mitochondrial citrate transporter Slc25A1, and the nuclear ATP-citrate lyase, in association with intracellular accumulation of citrate, the precursor for acetyl coenzyme A. These metabolic changes were coordinated with increased histone acetylation during transdifferentiation. CONCLUSION: Innate immune signaling promotes a glycolytic switch that is required for transdifferentiation, both processes being attenuated by ATP-citrate lyase knockdown. These data shed light on a novel link between metabolism and epigenetic modulation in transdifferentiation.

KW - cell transdifferentiation

KW - endothelium

KW - glycolysis

KW - mitochondria

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