Platelet-derived growth factor enhances in vitro erythropoiesis via stimulation of mesenchymal cells.

Abstract

The growth of erythroid colonies (from erythroid colonyforming cells) and erythroid bursts (from burst-forming cells IBFU-EI) is enhanced in the presence of serum as compared with plasma. A significant proportion of the enhanced growth is due to the platelet release product, platelet-derived growth factor (PDGF). Colony growth in cultures of whole marrow cells in platelet-poor plasma-derived serum (PDS) and erythropoietin was enhanced in a dose-dependent fashion by increasing concentrations of purified human PDGF with optimal enhancement at 12.5 ng/ml. However, no effect of plateletrelease products or PDGF was observed on nonadherent human marrow cells or peripheral blood BFU-E, suggesting that an accessory cell population was required for the effect of PDGF on hematopoietic progenitors. In a two-layer culture system, pure populations of fibroblasts or smooth muscle cells, known to be present in the marrow microenvironment, restored the response of nonadherent marrow cells in the overlayer to PDGF and also conferred responsiveness to peripheral blood BFU-E. Endothelial cells in the two-layer culture system and macrophages, in contrast, lacked the ability to restore the enhancing effect of PDGF. Because other platelet-release mitogenic products are also found in serum, a monospecific anti-PDGF IgG preparation was added to cultures grown in platelet rich plasma-derived serum. Only partial reduction in colony and burst growth was seen, suggesting that other platelet-release products were acting in this system. These results demonstrate that PDGF enhancement of human hematopoietic progenitor cell growth requires mesenchymal cells, and provide an example and mechanism by which growth factors may influence hematopoietic progenitors via cells of the marrow microenvironment.

Regulated production of a pleiotropic cytokine-platelet-derived growth factor--by differentiating erythroid cells in vitro and in vivo.

“…For several years it has been recognized that exogenous PDGF stimulates the proliferation and differentiation of erythroid cells in human bone marrow cultures (1,2). However, the physiological relevance of this observation was unknown.…”

“…The growth and differentiation of erythroid progenitors in vitro are enhanced markedly by the addition of platelet-derived growth factor (PDGF) (1,2). The mechanism through which PDGF exerts this effect is unknown.…”

“…Importantly, stimulation of normal erythropoiesis in vivo in mice treated either with phenylhydrazine or with erythropoietin increased PDGF levels in the spleen by 11-to 48-fold and 20-to 34-fold, respectively. These results strongly suggest a role for erythroid cell-derived PDGF in normal erythropoiesis and provide documentation of the regulated production of a pleiotropic cytokine by erythroid cells.The growth and differentiation of erythroid progenitors in vitro are enhanced markedly by the addition of platelet-derived growth factor (PDGF) (1,2). The mechanism through which PDGF exerts this effect is unknown.…”

Interactions of insulin, insulinlike growth factor II, and platelet-derived growth factor in erythropoietic culture.

“…Cells of mesenchymal origin are known to exert regulatory effects on the rate of hematopoietic cell growth (34, 35). Therefore, it is possible that insulin and IGF exert an indirect action similar to that postulated for PDGF (36), in which important cellular interactions within the local culture environment are activated that in turn accelerate erythroid differentiation and/or proliferation.…”

Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease

“…T lymphocytes and NK cells also express PDGFRb, and PDGF can modulate the pattern of T cell cytokines produced in vitro and NK cell cytotoxicity (Daynes et al, 1991;Gersuk et al, 1991). Under unsorted bone marrow culture conditions, PDGF is able to stimulate growth of primitive hematopoietic and erythroid precursors and promote megakaryocytopoiesis, most likely by stimulating mesenchymal cells to cytokine production (Delwiche et al, 1985;Yan et al, 1993;Yang et al, 1995). Targeted disruption of the PDGFRb gene in mice results in embryonic lethality just prior to birth, displaying hemorrhage, thrombocytopenia, anemia, dilated heart and defects in specialized smooth muscle cells present in vascular capillaries in brain (pericytes) and kidney (mesangial cells) Soriano, 1994) (Table 1).…”