Thrombopoietin: accumulating evidence for an important biological effect on the hematopoietic stem cell

Although it is clear that thrombopoietin is the primary regulator of thrombopoiesis, several lines of evidence indicate that the hormone affects multiple aspects of hematopoiesis: the in vivo administration of TPO increases marrow levels of erythroid, myeloid, and megakaryocytic progenitor cells and its genetic elimination or that of its receptor (c-mpl) reduces the numbers of these cells; all hematopoietic stem cells (HSCs) are c-mpl+; genetic elimination of c-mpl reduces the numbers of murine HSCs by 7-8-fold; and its null mutation in humans leads to congenital amegakaryocytic thrombocytopenia, a disorder that almost invariably leads to aplastic anemia. Recently, we have begun to explore the role of TPO in the HSC self-renewal and expansion that characterizes the post-stem-cell-transplantation period. Using limiting dilution cell transplantation analyses, we found that HSC self-renewal and expansion is reduced 10-20-fold after transplantation of normal stem cells into tpo null mice compared to their wild-type counterparts. Although the molecular mechanisms responsible for these findings are only now being explored, it is expected that a greater understanding of the roles played by TPO in HSC physiology will lead to novel therapeutic opportunities.