Granulocyte-monocyte Progenitor Cells Research Articles

The effect of lithium on murine hematopoiesis in a liquid culture system.

Lithium carbonate has been shown to increase granulocyte production. We studied the effect of lithium on murine hematopoiesis in a liquid culture system providing for the prolonged growth of stem cells and their progeny. After one week of incubation, lithium, at a supernatant concentration of 1 mmol per liter, increased murine pluripotent stem cells (CFU-S, or colony-forming units in spleen) to 232 per cent of control values (P less than 0.001), granulocyte-monocyte progenitor cells (CFU-C, or colony-forming units in culture) to 218 per cent of control values (P less than 0.0001), granulocytes to 125 per cent of control values (P less than 0.01), and megakaryocytes to 246 per cent of control values (P less than 0.001). These increases were associated with transient elevations in colony-stimulatory activity. Prolonged exposure to lithium (three to 12 weeks) was associated with a dose-dependent progressive depletion of stem cells and their progeny. Lithium enhancement of granulopoiesis may be explained by primary stimulation of the pluripotent stem cell. Prolonged proliferative stress induced by lithium when the stem-cell reserve is limited may be associated with diminished replicative potential of the stem cells and rapid depletion of cells.

Studies on the pathogenesis of refractory anemia

Nine patients with refractory anemia were studied using the soft agar marrow culture assay (CFU-c) to identify granulocyte-monocyte progenitor cells. Patients' marrows were then cocultured with normal marrow to identify suppressor cells that inhibit normal colony formation. Three of nine patients had low colony formation and no suppression in coculture. These patients may have a defect intrinsic to the marrow granulocyte-monocyte progenitor cell, termed type I. Three of nine patients had normal colony formation and no suppression in coculture, possibly representing a type II defect in the hemopoietic environment. Three of nine patients had low colony formation in the CFU-c assay and their marrow contained cells that suppressed colony formation by normal marrow in coculture. This defect, termed type III, may result from suppressor cells. Thus, refractory anemia may be a syndrome resulting from at least three different pathogenetic mechanisms involving defects in (1) stem cells, (2) the marrow environment or (3) suppressor cells. This may represent one end of the spectrum of pancytopenia with diminished cellularity (aplastic anemia) or normal cellularity (refractory anemia) resulting from similar mechanisms.

Inhibition In Vivo of Mouse Granulopoiesis by Cell-free Activity Derived From Human Polymorphonuclear Neutrophils

AbstractCell-free extracts from human polymorphonuclear neutrophils (PMN) inhibited rebound granulopoiesis in the bone marrow and spleen of mice pretreated with cyclophosphamide to remove endogenous PMN. Absolute numbers of granulocyte-monocyte progenitor cells (CFU-C) and net endogenous colony-stimulating activity (CSA) production were found to be increased 3 days after cyclophosphamide in the bone marrow and 6 days after in the spleen. Administration of PMN extract to the drug-treated mice prior to rebound granulopoiesis substantially decreased CSA production and CFU-C but not spleen B lymphocyte colony-forming cells. In addition, mice treated with PMN extract had decreased levels of CSA in serum and in conditioned medium of marrow-free bone, heart, and lung cultures. Inhibition was reversed by injection of bacterial lipopolysaccharide. Extracts from PMN of patients with chronic myelogenous leukemia, inactive in vitro, had no effect in vivo. These results demonstrate that inhibitory activity derived from PMN can control granulopoiesis in vivo.

Inhibition in vivo of mouse granulopoiesis by cell-free activity derived from human polymorphonuclear neutrophils

Cell-free extracts from human polymorphonuclear neutrophils (PMN) inhibited rebound granulopoiesis in the bone marrow and spleen of mice pretreated with cyclophosphamide to remove endogenous PMN. Absolute numbers of granulocytemonocyte progenitor cells (CFU-C) and net endogenous colony-stimulating activity (CSA) production were found to be increased 3 days after cyclophosphamide in the bone marrow and 6 days after in the spleen. Administration of PMN extract to the drug- treated mice prior to rebound granulopoiesis substantially decreased CSA production and CFU-C but not spleen B lymphocyte colony-forming cells. In addition, mice treated with PMN extract had decreased levels of CSA in serum and in conditioned medium of marrow-free bone, heart, and lung cultures. Inhibition was reversed by injection of bacterial lipopolysaccharide. Extracts from PMN of patients with chronic myelogenous leukemia, inactive in vitro, had no effect in vivo. These results demonstrate that inhibitory activity derived from PMN can control granulopoiesis in vivo.

Thyroid hormones stimulate erythropoiesis in vitro.

Thyroid hormones have important effects on erythropoiesis in man and animals. We performed in vitro culture studies with murine and human bone marrow in order to define the interaction of these hormones with erythroid and granulocyte-monocyte progenitor cells. The methylcellulose clonogenic assay was used with the appropriate addition of erythropoietin or colony-stimulating activity. L-thyroxine, D-thyroxine and L-triiodothyronine potentiated erythropoientin-stimulated erythroid colony formation in concentrations of 50-100 ng/ml. These hormones had no effect on granulocyte-monocyte colony formation at concentrations up to 500 ng/ml. Testing of various thyroid analogues showed no clear correlation between potentiation of erythropoiesis and known calorigenic potency. Reverse triiodothyronine also had potentiating activity in this system. The active thyroid hormones stimulated erythroid colony formation at several concentrations of erythropoietin but could not substitute for erythropoietin. These data suggest that thyroid hormones have a direct effect on erythroid precursor proliferative capacity, a finding which may have relevance to the mechanism of erythropoietic dysfunction in human thyroid disease.

Amphotericin inhibition of hematopoiesis in vitro.

The effect of amphotericin B on human and murine hematopoiesis was studied in vitro using assays for erythroid and myeloid colony-forming cells. Amphotericin consistently inhibited colony formation by erythroid and granulocyte-monocyte progenitor cells. Clear effects were observable at amphotericin concentrations of 1.0 microgram/ml, and concentrations of 2.0 microgram/ml caused approximately 50-60% inhibition of cloning of both murine and normal human bone marrow. These data suggest that amphotericin, in concentrations achieved in therapy, can impair hematopoiesis by a direct effect on precursor cells.