Murine hematopoietic stem cell and stromal responses to clinically-related, fractionated radiotherapy (FxRT)

Full text: While the hematopoietic response to acute and abbreviated fractionated exposures of ionizing radiation is well documented, information pertaining to a more clinically-relevant course of radiotherapy is limited. For this reason, and to establish a model for future investigation, we have designed a series of studies to define the response of the blood forming and supportive stromal compartments of the marrow to a localized, fractionated course of radiotherapy [FxRT; 2.0 Gy (q24h x 5) 74 Gy] in the C57Bl/6 mouse. The hematopoietic progenitor (CFU-M, CFU-HPP) and the cobblestone-forming cell (CAFC, day 7, 14, 21 and 28) assays were used as end points for the blood forming compartment and the long-term bone marrow culture (LTBMC) to assess stromal integrity. Both during and subsequent to FxRT, hematopoietic activity in the irradiated femur was significantly dampened, although an abortive attempt at recovery was observed subsequent to the completion of FxRT. Moreover, both the CAFC subpopulations as well as the functional integrity of LTBMC generated from the irradiated femur were significantly compromised by FxRT. Of interest, restoration of the more primitive CAFC subpopulations to near normal levels was observed in the absence of a comparable recovery of the more mature CAFC subpopulations and the restoration of stromal integrity to the irradiated marrow. As a result, the data are consistent with the generation of a persisting FxRT-induced lesion in the microenvironmental stroma that effectively interferes with the normal regulation of hematopoietic differentiation and the recovery of hematopoietic activity in the irradiated marrow