Identification of Quantitative Trait Loci Regulating Steady State Hematopoiesis and Progenitor Mobilization in AKRB6F2 Mice.

The hematopoietic system is a complex organized tissue with a hierarchical structure. Identification of organizational pathways within the hematopoietic system would be relevant for a better understanding of hematopoiesis in health and disease. We have analyzed numerous hematopoietic parameters in AKRB6F2 mice, a cross between AKR and C57Bl/6 mice that differ in various stem cell traits. Specifically, we have measured stem cell numbers, progenitor cell cycling, G-CSF induced stem cell mobilization, as well as neutrophil numbers in blood and bone marrow. We used these data to map quantitative trait loci for these parameters in order to assess whether distinct traits are associated with each other and by which genetic loci these parameters are regulated. When the different hematopoietic parameters were compared, surprisingly few significant correlations were found and only two quantitative trait loci (QTL) could be identified for all hematopoietic parameters. We confirm that a region on chromosome 11 is involved in progenitor cell cycling and we found an additional QTL for stem cell numbers, measured as CAFC day 35 per femur, on chromosome 2. A suggestive QTL was found for the number of progenitors in the bone marrow and the number of neutrophils in the blood. In the first of two series of offspring mice we found a strong association between stem cell mobilization and B6 alleles at the chromosome 3 locus D3Mit88 or AKR alleles on chromosome 15 (D15Mit241). However, this could not be confirmed in the second series. In addition, breeding of an F3 generation from the best mobilizers (6479 ± 1544 CFU-GM/ml blood vs. 3481 ± 3076 overall) of each series did not result in high mobilization capacity of the offspring (1333 ± 844 CFU-GM/ml). Taken together, our data illustrates that different hematopoietic parameters are independently regulated. This suggests that hematopoiesis is highly structured and regulation at all levels of stem cell development can lead to distinct mechanisms of stem cell maintenance resulting in normal levels of mature blood cells. Additionally, variation based on epigenetic determinants that do not transmit to the next generation may play an important role in the regulation of steady state hematopoiesis and stem cell mobilization.