The early progenitors of the lymphoid lineages in the mouse are not yet clearly defined. New studies regarding the nature of the lymphoid progenitors have suggested that an intermediate progenitor with potential to differentiate only into the T and B lineages (common lymphoid progenitor) can be isolated from adult mouse bone marrow. Other studies have demonstrated progenitors with restricted lymphoid-myeloid potential in fetal development, but have failed to confirm the existence of a common lymphoid progenitor. A newly developed selection protocol that separates hematopoietic stem cells from progenitor cells will be utilized to investigate the characteristics of early progenitors for the lymphoid lineages in adult mouse bone marrow. The selection protocol will also be refined to allow isolation of early myeloid and erythroid progenitors. Using these tools, three Specific Aims will be addressed. In the first Aim, the early stages of B-cell development will be investigated to determine the identity, growth requirements, and functional potential of cells defined as B-cell progenitors by the new selection protocol. In the second Aim, an in vivo T-cell development assay will be utilized to isolate and characterize bone marrow progenitors able to home to and proliferate within the thymus.
The third Aim will focus on progenitors for megakaryocyte, erythroid, and dendritic cell lineages and will define transplantation and cell culture growth characteristics of isolated progenitor subsets. These studies will define the early stages in the process of lineage commitment in mouse hematopoiesis, providing a framework within which future studies aimed at mechanistic analysis of this process can be initiated. In addition, the feasibility of utilizing progenitor populations as a means to replenish specific blood lineages through transplantation will be evaluated. Collectively, the proposed experiments will contribute to both basic and clinical research efforts aimed at understanding the nature of early lineage commitment in hematopoiesis and the potential of hematopoietic progenitor cells to be utilized in clinical transplantation settings.
