Anatomical Compartments Modulate the Response of Human Hematopoietic Cells to Mitogenic Signaling, In Vivo.

Hematopoietic cells can respond differently to a mitogenic signal depending on whether the signal is delivered in vitro or in vivo. Results presented here suggest that the compartment in which a human hematopoietic progenitor resides can influence its response to a proliferative stimulus. An ectopically expressed conditional derivative of the thrombopoietin receptor (F36VMpl) in human cord blood CD34⁺ cells induces, upon provision of an agonist ligand, the differentiation (but not expansion) of transduced human burst forming units erythroid (BFUe) in culture. Here we show that upon transplantation into immune deficient mice, F36VMpl-expressing human BFUe and multipotential mixed progenitors (CFU-mix) decline in the marrows of ligand-exposed mice, replaced by a 12–17 fold expansion of differentiated erythroid precursors. In contrast, F36VMpl signaling dramatically expands BFUe and CFUmix in the spleen. Clonal analysis is consistent with the interpretation that F36Vmpl signaling induces an in situ expansion of BFUe and CFUmix in the spleen. In aggregate, these findings suggest that differences in environmental signals present in the marrow versus spleen can regulate the differentiation versus expansion of BFUe and CFU-mix.