Lifelong residual bone marrow damage in murine survivors of the hematopoietic acute radiation syndrome (H-ARS): a compilation of studies comprising the Indiana University experience

Abstract

Accurate analyses of the delayed effects of acute radiation exposure (DEARE) in survivors of the hematopoietic acute radiation syndrome (H-ARS) are hampered by low numbers of mice for examination due to high lethality from the acute syndrome, increased morbidity and mortality in survivors, high cost of husbandry for long-term studies, biological variability, and inconsistencies of models from different laboratories complicating meta-analyses. To address this, a compilation of 38 similar H-ARS studies conducted over a seven-year period in the authors’ laboratory, comprising more than 1,500 irradiated young adult C57BL/6 mice and almost 600 day-30 survivors, was assessed for hematopoietic DEARE at various times up to 30 months of age. Significant loss of long-term repopulating potential of phenotypically-defined primitive hematopoietic stem cells (HSC) was documented in H-ARS survivors, as well as significant decreases in all hematopoietic lineages in peripheral blood, prominent myeloid skew, significantly decreased bone marrow cellularity and numbers of lineage-negative Sca-1+ cKit+ CD150+ cells (KSLCD150+; the phenotype known to be enriched for HSC), and increased cycling of KSLCD150+ cells. Studies interrogating the phenotype of bone marrow cells capable of initiation of suspension cultures and engraftment in competitive transplantation assays documented the phenotype of HSC in H-ARS survivors to be the same as that in non-irradiated age-matched controls. This compilation study adds rigor and validity to our initial findings of persistent hematopoietic dysfunction in H-ARS survivors that arises at the level of the HSC and which affects all classes of hematopoietic cells for the life of the survivor.