Inhibiting Glycogen Synthase Kinase-3 Mitigates the Hematopoietic Acute Radiation Syndrome in a Sex- and Strain-dependent Manner in Mice
| Autor: | Patrick Oh, Chang-Lung Lee, David G. Kirsch, Andrea R. Daniel, Lixia Luo, Yan Ma |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Indoles Epidemiology Health Toxicology and Mutagenesis Mice Transgenic Radiation-Protective Agents Pharmacology Article 030218 nuclear medicine & medical imaging Maleimides Glycogen Synthase Kinase 3 Mice 03 medical and health sciences Sex Factors 0302 clinical medicine Species Specificity SOX2 Bone Marrow GSK-3 Animals Medicine Radiology Nuclear Medicine and imaging Progenitor cell Glycogen synthase Protein Kinase Inhibitors biology Kinase business.industry Wnt signaling pathway Total body irradiation Hematopoiesis Mice Inbred C57BL Haematopoiesis Acute Radiation Syndrome 030220 oncology & carcinogenesis biology.protein Female business |
| Zdroj: | Health Phys |
| ISSN: | 1538-5159 0017-9078 |
| Popis: | The Radiation and Nuclear Countermeasures Program at the National Institute of Allergy and Infectious Diseases (NIAID) mandated that medical countermeasure for treating the Acute Radiation Syndrome (ARS) must have efficacy when administered at least 24 hours after radiation exposure. At this time point, many cells within key target tissues, such as the hematopoietic system and the gastrointestinal (GI) tract will already be dead. Therefore, drugs that promote the regeneration of surviving cells may improve outcomes. The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) regulates stem and progenitor cell self-renewal and regeneration in the hematopoietic and GI compartments. We tested inhibition of GSK-3β by SB216763 24 hours after total body irradiation (TBI) and sub-total body Irradiation (SBI). Here, we show that subcutaneous administration of SB216763 promotes the regeneration of surviving hematopoietic stem/progenitor cells (HSPCs) including myeloid progenitor cells and improves survival of C57Bl/6 male mice when administered 24 hours after TBI. However, these results were not recapitulated in female C57Bl/6 animals suggesting a sex difference in GSK-3β signaling in HSPCs. Subcutaneous administration of SB216763 in male mice stimulated activation of Sox2 transcription, but failed to induce Sox2 transcription in female C57Bl/6 mice. Using TCF/lef-GFP reporter mice we examined Wnt signaling in HSPCs of irradiated male and female mice treated with SB216763. GSK-3 inhibition elevated Wnt reporter activity in HSPCs isolated from male but not female mice. SB216763 did not mitigate hematopoietic ARS in males or females of a second strain of wild type mice, C3H. In addition, administration of SB216763 did not mitigate hematopoietic ARS beyond the currently available standard approved therapy of ciprofloxacin and granulocyte-colony stimulating factor (G-CSF) in male C57Bl/6 mice. Further, SB216763 did not mitigate GI-ARS after SBI in C57Bl/6 male mice. The lack of efficacy in both sexes and multiple strains of mice indicate that SB216763 is not suitable for further drug development as a mitigator of ARS. Our studies demonstrate that activation of Wnt signaling in HSPC promotes hematopoietic regeneration following radiation exposure and targeting this pathway downstream of GSK-3β may mitigate ARS in a sex and strain independent manner. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|