Receptor Specificity in the Self-Renewal, Survival and Differentiation of Hematopoietic Stem and Progenitor Cells In Vitro and In Vivo.

Hematopoietic growth factors have had many applications in clinical medicine. However the entry of new growth factors into the clinic has been hampered by the ability of many ligands to affect non-targeted tissues, or to activate more than one receptor type in the targeted tissue. Here we test whether receptors, rather than ligands, can be used to differentially regulate hematopoiesis in vitro and in vivo. Using modified receptors whose activity is solely dependent on a synthetic ligand, called a chemical inducer of dimerization (CID), we compared a conditional derivative of fibroblast growth factor receptor -1 (F36VFGFR1) with an analogous derivative of the thrombopoietin receptor (F36VMpl) in the transduced bone marrow cells of mice. While both receptors allowed for the sustained expansion of transduced marrow cells in culture, only F36VFGFR1 allowed for the expansion of short term repopulating HSCs, and the survival of long term repopulating HSCs, in culture. Both receptors supported the CID dependent expansion of erythroid cells in vivo, however F36VFGFR1 was much more potent, and also induced a marked CID-dependent expansion of platelets and granulocytes, lineages in which F36VMpl had little effect. Cultures in the presence of inhibitors of cell signaling showed a surprising amount of overlap, with both receptors exhibiting equal susceptibility to Jak2 inhibition, whereas F36VFGFR1 was relatively more sensitive to inhibitors of src kinases and phospholipase Cgamma.