GROWTH-HORMONE, GROWTH-FACTORS AND HEMATOPOIESIS

Hypocellularity of primary lymphoid organs is a distinctive and reprod ucible characteristic of aged humans and animals, Similar changes have been reported in both hypophysectomized and dwarf rodents, In the bon e marrow of these animals, there is an associated reduction in the num ber of erythroid, lymphoid and myeloid elements, Implantation of growt h hormone (GH)-secreting GH(3) pituitary cells or infusion of growth h ormone into aged rodents dramatically improves cellularity of both the thymus gland and bone marrow, At present it is unknown whether these effects are due to direct effects of growth hormone on hematopoietic c ells or if they are caused by the induction of insulin-like growth fac tor-1 (IGF-1) synthesis. We recently discovered that colony-stimulatin g factor-1 (CSF-1) and interleukin-3 (IL-3) induce expression and synt hesis of the IGF-1 peptide in murine bone marrow cells. Transcripts fo r IGF-1 increase approximately 50-fold during differentiation over the negligible levels that are expressed in freshly isolated bone marrow cells, Two potential functions of macrophage-derived IGF-I are to: (a) increase the proliferation of early or committed bone marrow progenit ors and (b) reduce their rate of cell death, In support of the first p ossibility, IGF binding protein-3 significantly inhibits the prolifera tion of CSF-1-treated bone marrow cells and this inhibition can be rev ersed by addition of exogenous IGF-1, In support of the second possibi lity, we have induced apoptosis of both nonadherent bone marrow cells and a myeloid progenitor cell line by depriving these cells of CSFs, P reliminary results indicate that addition of IGF-1 to these cells redu ces apoptotic cell death by 50%, These data establish that two differe nt CSFs, CSF-1 and IL-3, induce abundant expression of IGF-1 as these cells differentiate into more mature hematopoietic cells. This model o ffers a novel approach for investigating the developmental expression of IGF-1 during defined differentiation pathways of hematopoietic cell s, If IGF-1 is indeed proven to act as a survival factor for hematopoi etic progenitors, these data would support the idea that the hypocellu larity of primary lymphoid tissues in aged animals is related to the l imited availability to these cells of either growth hormone or IGF-1.