Stem cell self-renewal and lineage commitment are central to the maintenance of normal hematopoiesis. Decisions about self-renewal and commitment are made on the level of a single stem cell, and thus require examination on the clonal level. We have developed a highly effective in vitro method to obtain clonal, in vivo repopulating stem cells. Amongst the clonal stem cells, we identified a subset of stem cells that produced mature progeny that were noticeably skewed to either the myeloid or the lymphoid lineages. We call this new population lineage dominant stem cell. We found that lineage dominant stem cells: 1) contribute to all hematopoietic lineages, albeit with a noticeably skewed ratio; 2) can have extensive self-renewal capacity; 3) the lineage dominance is stable through multiple rounds of transplantation. Collectively, the data show that lineage dominant stem cells are a distinct class of primitive hematopoietic stem cells. We hypothesize that lineage dominant stem cells have partially committed to the myeloid or lymphoid lineages. The early commitment steps result in a competitive disadvantage of the progeny in the under-represented lineage. This may cause a reduced numbers of precursors and/or a reduced proliferative capacity of the mature cells. Our preliminary data suggest that both mechanisms contribute to lineage dominance. To test this hypothesis we propose 4 specific aims: 1) How many stem cells are generated in the limiting dilution cultures? 2) Is lineage dominance due to decreased fitness of a lineage? 3) Is lineage dominance influenced by environmental signals? 4) Can stem cells at the early stages of myeloid or lymphoid lineage commitment be separated? A better understanding of the causes and consequences of stem cell commitment on the single stem cell level would be beneficial for the ex vivo manipulation of stem cells, in curative stem cell transplantation, and may aid in the understanding of leukemogenesis.
| Muller-Sieburg, Christa E; Sieburg, Hans B; Bernitz, Jeff M et al. (2012) Stem cell heterogeneity: implications for aging and regenerative medicine. Blood 119:3900-7 |
| Sieburg, Hans B; Rezner, Betsy D; Muller-Sieburg, Christa E (2011) Predicting clonal self-renewal and extinction of hematopoietic stem cells. Proc Natl Acad Sci U S A 108:4370-5 |
| Muller-Sieburg, C E; Sieburg, H B (2006) The GOD of hematopoietic stem cells: a clonal diversity model of the stem cell compartment. Cell Cycle 5:394-8 |
| Sieburg, Hans B; Cho, Rebecca H; Dykstra, Brad et al. (2006) The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood 107:2311-6 |
