Monoclonal derivation of mouse myeloid and lymphoid lineages from totipotent hematopoietic stem cells experimentally engrafted in fetal hosts.

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Mutant mouse fetuses with a hematopoietic stem cell defect were injected with a mixture of two normal strains of fetal liver cells to test the possibility of seeding with single stem cells and of deriving all hematopoietic lineages clonally. Recipients were either Wf/Wf, with a mild endogenous defect offering only marginal selective advantage to a normal donor cell, or W/W, with a severe defect. Among 11 Wf/Wf animals with long-term grafts, 8 had only one or the other of the donor strains. Some of these individuals must have been seeded by only a single donor cell (P = 0.1); the frequency of this event was at least 20% (90% confidence) and most likely 50% of the cases. Cell-specific strain markers in myeloid and lymphoid lineages reinforced the likelihood that renewal and differentiation had occurred from a totipotent hematopoietic stem cell. In a smaller W/W group, some hosts were seeded by at most two cells (P = 0.1), and single-cell seeding could not be ruled out. The experiment allows stem cell pedigrees to be examined during the normal developmental progression. In both groups observed here, some mice displayed a regular and complementary rise and fall in proportions of cells of different genotypes, thereby suggesting clonal succession in a hierarchy of stem cell compartments. This transplant system also offers advantages for future experiments on regulated expression in vivo of genes transferred (in vitro) into totipotent hematopoietic stem cells.

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