Long-Term Hematopoietic Stem Cell Damage in a Murine Model of the Hematopoietic Syndrome of the Acute Radiation Syndrome

Abstract

Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sub-lethal doses of radiation and time points within a few months of exposure. In this study, we examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 months post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient as long as 16months post-TBI compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSC is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (lin-, KSL, KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points.

CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche

“…BM cells from irradiated mice exhibit a persistent engraftment defect postirradiation, 24,25 whereas those from mice treated with 5-FU engraft successfully. 26 Expression of CD166 on LSK from sublethally irradiated mice was significantly reduced ( Figure 4F).…”

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

“…The hematopoietic system is highly sensitive to IR, and in particular, IR doses beyond 2 Gy can lead to myelosuppression that is characterized by neutropenia, lymphocytopenia, and thrombocytopenia. Collectively, hematopoietic acute radiation syndrome (H-ARS) increases the risk of infection, bleeding, and death (1)(2)(3)(4)(5)(6)(7)(8)(9). There is an unmet need for effective interventions to mitigate the progression of H-ARS after IR exposure (10).…”

Kojic Acid Protects C57BL/6 Mice from Gamma-irradiation Induced Damage

“…Exposure of animals to ionizing radiation can induce long-term hematopoietic cells damage, which is mainly the self-renewal damage for hematopoietic stem cells (HSCs) (Chua et al, 2012). Wang et al (2006) found C57BL/6 mice exposed to a sub-lethal dose of gamma irradiation induced a persistent reduction in LKS+ HSCs.…”