The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids

Bryan Kuo, Erzsébet Szabó, Sue Lee, Andrea Balogh, Derek Norman, Asuka Inoue, Yuki Ono, Junken Aoki, Gabor Tigyi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Rapidly proliferating cells are highly sensitive to ionizing radiation and can undergo apoptosis if the oxidative and genotoxic injury exceed the defensive and regenerative capacity of the cell. Our earlier work has established the antiapoptotic action of the growth factor-like lipid mediator lysophosphatidic acid (LPA). Activation of the LPA2 GPCR has been hypothesized to elicit antiapoptotic and regenerative actions of LPA. Based on this hypothesis we developed a novel nonlipid agonist of LPA2, which we designated Radioprotectin-1 (RP-1). We tested RP-1 at the six murine LPA GPCR subtypes using the transforming growth factor alpha shedding assay and found that it had a 25 nM EC50 that is similar to that of LPA18:1 at 32 nM. RP-1 effectively reduced apoptosis induced by γ-irradiation and the radiomimetic drug Adriamycin only in cells that expressed LPA2 either endogenously or after transfection. RP-1 reduced γ-H2AX levels in irradiated mouse embryonic fibroblasts transduced with the human LPA2 GPCR but was ineffective in vector transduced MEF control cells and significantly increased clonogenic survival after γ-irradiation. γ-Irradiation induced the expression of lpar2 transcripts that was further enhanced by RP-1 exposure within 30 min after irradiation. RP-1 decreased the mortality of C57BL/6 mice in models of the hematopoietic and gastrointestinal acute radiation syndromes. Using Lgr5-EGFP-CreER;Tdtomatoflox transgenic mice, we found that RP-1 increased the survival and growth of intestinal enteroids via the enhanced survival of Lgr5+ intestinal stem cells. Taken together, our results suggest that the LPA2-specific agonist RP-1 exerts its radioprotective and radiomitigative action through specific activation of the upregulated LPA2 GPCR in Lgr5+ stem cells.

Original languageEnglish (US)
Pages (from-to)23-33
Number of pages11
JournalCellular Signalling
Volume51
DOIs
StatePublished - Nov 1 2018

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Lysophosphatidic Acid Receptors
Radiation Injuries
Stem Cells
Survival
Acute Radiation Syndrome
Apoptosis
Transforming Growth Factor alpha
Ionizing Radiation
Inbred C57BL Mouse
Doxorubicin
Transgenic Mice
Transfection
Intercellular Signaling Peptides and Proteins
Fibroblasts
Lipids
Mortality
Wounds and Injuries
Growth
Pharmaceutical Preparations
lysophosphatidic acid

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids. / Kuo, Bryan; Szabó, Erzsébet; Lee, Sue; Balogh, Andrea; Norman, Derek; Inoue, Asuka; Ono, Yuki; Aoki, Junken; Tigyi, Gabor.

In: Cellular Signalling, Vol. 51, 01.11.2018, p. 23-33.

Research output: Contribution to journalArticle

Kuo, Bryan ; Szabó, Erzsébet ; Lee, Sue ; Balogh, Andrea ; Norman, Derek ; Inoue, Asuka ; Ono, Yuki ; Aoki, Junken ; Tigyi, Gabor. / The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids. In: Cellular Signalling. 2018 ; Vol. 51. pp. 23-33.
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AU - Kuo, Bryan

AU - Szabó, Erzsébet

AU - Lee, Sue

AU - Balogh, Andrea

AU - Norman, Derek

AU - Inoue, Asuka

AU - Ono, Yuki

AU - Aoki, Junken

AU - Tigyi, Gabor

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AB - Rapidly proliferating cells are highly sensitive to ionizing radiation and can undergo apoptosis if the oxidative and genotoxic injury exceed the defensive and regenerative capacity of the cell. Our earlier work has established the antiapoptotic action of the growth factor-like lipid mediator lysophosphatidic acid (LPA). Activation of the LPA2 GPCR has been hypothesized to elicit antiapoptotic and regenerative actions of LPA. Based on this hypothesis we developed a novel nonlipid agonist of LPA2, which we designated Radioprotectin-1 (RP-1). We tested RP-1 at the six murine LPA GPCR subtypes using the transforming growth factor alpha shedding assay and found that it had a 25 nM EC50 that is similar to that of LPA18:1 at 32 nM. RP-1 effectively reduced apoptosis induced by γ-irradiation and the radiomimetic drug Adriamycin only in cells that expressed LPA2 either endogenously or after transfection. RP-1 reduced γ-H2AX levels in irradiated mouse embryonic fibroblasts transduced with the human LPA2 GPCR but was ineffective in vector transduced MEF control cells and significantly increased clonogenic survival after γ-irradiation. γ-Irradiation induced the expression of lpar2 transcripts that was further enhanced by RP-1 exposure within 30 min after irradiation. RP-1 decreased the mortality of C57BL/6 mice in models of the hematopoietic and gastrointestinal acute radiation syndromes. Using Lgr5-EGFP-CreER;Tdtomatoflox transgenic mice, we found that RP-1 increased the survival and growth of intestinal enteroids via the enhanced survival of Lgr5+ intestinal stem cells. Taken together, our results suggest that the LPA2-specific agonist RP-1 exerts its radioprotective and radiomitigative action through specific activation of the upregulated LPA2 GPCR in Lgr5+ stem cells.

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