A Single Radioprotective Dose of Prostaglandin E
| Autor: | Andrea M, Patterson, Liqiong, Liu, Carol H, Sampson, P Artur, Plett, Hongge, Li, Pratibha, Singh, Khalid S, Mohammad, Jonathan, Hoggatt, Maegan L, Capitano, Christie M, Orschell, Louis M, Pelus |
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| Rok vydání: | 2020 |
| Předmět: |
p53
hematopoietic regeneration bone marrow Transcription Genetic Apoptosis Radiation-Protective Agents Dinoprostone Article stem cells Radiation Ionizing Animals Gene Regulatory Networks 16 16-dimethyl PGE2 Cell Cycle RNA sequencing Hematopoietic Stem Cells Hematopoiesis Mice Inbred C57BL radiation Gene Expression Regulation DNA damage cell cycle prostaglandin DNA Damage Signal Transduction Transcription Factors |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary Ionizing radiation exposure results in acute and delayed bone marrow suppression. Treatment of mice with 16,16-dimethyl prostaglandin E2 (dmPGE2) prior to lethal ionizing radiation (IR) facilitates survival, but the cellular and molecular mechanisms are unclear. In this study we show that dmPGE2 attenuates loss and enhances recovery of bone marrow cellularity, corresponding to a less severe hematopoietic stem cell nadir, and significantly preserves long-term repopulation capacity and progenitor cell function. Mechanistically, dmPGE2 suppressed hematopoietic stem cell (HSC) proliferation through 24 h post IR, which correlated with fewer DNA double-strand breaks and attenuation of apoptosis, mitochondrial compromise, oxidative stress, and senescence. RNA sequencing of HSCs at 1 h and 24 h post IR identified a predominant interference with IR-induced p53-downstream gene expression at 1 h, and confirmed the suppression of IR-induced cell-cycle genes at 24 h. These data identify mechanisms of dmPGE2 radioprotection and its potential role as a medical countermeasure against radiation exposure. Graphical Abstract Highlights • Treatment with dmPGE2 prior to lethal IR attenuates early hematopoietic cell loss • IR-induced apoptotic gene expression is blocked in HSCs by dmPGE2 • dmPGE2 temporarily suppresses proliferation of HSCs and HPCs in vivo • Early IR-induced cycling, DNA damage, and their sequelae were attenuated in HSCs In this article, Pelus, Orschell, and colleagues demonstrate that dmPGE2 protection from lethal radiation preserves HSC numbers and repopulating capacity, which is associated with attenuation of HSC cycling and DNA damage accumulation within the first critical day. Genomically, dmPGE2 predominantly blocks HSC induction of p53-regulated apoptotic genes within 1 h of irradiation, altogether promoting hematopoietic recovery and survival. |
| Databáze: | OpenAIRE |
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