Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice.

Abstract

We have studied contributions to hematopoiesis of genetically distinct stem cell populations in allophenic mice. Chimeras were made by aggregating embryos of inbred strains known to differ with respect to stem cell population kinetics. One partner strain (DBA/2) has previously been shown to normally have a stem cell (CFU-S) population of which 24% are in S-phase of the cell cycle, whereas the homologous population of the other partner strain (C57BL/6) was characterized by having only 2.6% in cycle (7). Contributions of the chimeric stem cell population to mature blood cell pools were studied throughout the life of the mice and intrinsic differences in stem cell function and aging were reflected in dynamic patterns of blood cell composition. The DBA/2 stem cell population was eclipsed by stem cells of the C57BL/6 genotype and, after 1.5-3 yr, the hemato-lymphoid composition of 22 of 27 mice studied for this long had shifted by at least 25 percentage points toward the C57BL/6 genotype. 8 of the 27 had hematolymphoid populations solely of C57BL/6 origin. To test whether or not a population of stem cells with an inherently higher cycling rate (DBA/2) might have a competitive advantage during repopulation, we engrafted allophenic marrow into lethally irradiated (C57BL/6 x DBA/2)F1 recipients. DBA/2 hematopoiesis was predominant early, far outstripping its representation in the marrow graft. Perhaps as a consequence of inherently greater DBA/2 stem cell proliferation, the populations of developmentally more restricted precursor populations (CFU-E, BFU-E, CFU-GM, CFU-GEMM) showed an overwhelming DBA/2 bias in the first 2-3 mo after engraftment. However, as in the allophenic mice themselves during the aging process, the C57BL/6 genotypic representation was ascendant over the subsequent months. The shift toward C57BL/6 genotype was first documented in the marrow and spleen precursor cell populations and was subsequently reflected in the circulating, mature blood cells. Bone marrow-derived stromal cell cultures from engrafted mice were studied and genotypic analyses showed donor representation in stromal cell populations that reflected donor hematopoietic contributions in the same recipient. Results from these studies involving two in vivo settings (allophenic mice and engraftment by allophenic marrow) are consistent with the notion that a cell autonomous difference in stem cell proliferation confers on one population a competitive repopulating advantage, but at the expense of longevity.