Lee Levitt

Hematopoietic stem cells.

(First of Three Parts) IN man, most tissues consist primarily of differentiated cells that normally show little evidence of proliferation and self-renewal. However, the gastrointestinal mucosal cel...

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.

Further studies on the mechanism of marrow granulocytic hyperplasia in mice chronically injected with endotoxin

Marrow granulocytic hyperplasia occurs regularly in mice injected with endotoxin for 7‐30 d, despite minimal elevations of serum colony‐stimulating activity (CSA). Alterations in marrow granulocyte‐monocyte progenitor (CFU‐C) number or changes in marrow cell cycle status do not explain this hyperplasia. We have studied other mechanisms which may explain this increased granulopoiesis. CF1, BDF1 or C57bl/6J mice were injected with 10 μg of S. typhosa, endotoxin i.p. daily for 7‐20 d. Control and endotoxin injected (tolerant) sera, each with identical levels of CSA, were assayed against control marrow cells stimulated with supramaximal amounts of CSA to assess the role of serum potentiators in augmenting granulopoiesis. In six separate experiments, tolerant sera, over a 30‐fold concentration range, produced a 1.7–4.0‐fold potentiation of colony growth compared to control sera (P<0.001). No increased tolerant sera potentiation was seen over a similar concentration range when assayed against tolerant marrow. Tolerant and control splenic conditioned media, both dialysed and non‐dialysed, failed to potentiate control marrow colony growth. Tolerant marrow stem cells did not show changes in CSA sensitivity, colony size distribution or differentiation, and tolerant bone or bone marrow cells did not produce increased amounts of CSA. We conclude that serum factors separate from CSA may in part explain the increased granulopoiesis seen in endotoxin injected mice. The failure of tolerant sera to potentiate tolerant marrow growth in vitro, may reflect prior in vivo, exposure of marrow to these potentiating factor(s).

JAK2 Mutations and Coronary Ischemia

To the Editor: The chronic myeloproliferative disorders are clonal marrow neoplasms that are often associated with arterial or venous thromboses and microcirculatory disturbances.1 Certain thrombot...

Studies on the Regulation of Diffusion Chamber Granulopoiesis

We have evaluated the role of colony-stimulating activity (CSA) and stem cells in diffusion chamber (DC) myelopoiesis. CF1 host mice were implanted with DC with 0.5 x 106 normal marrow cells and then injected for 3–4 days intravenously with 5 μg Salmonella typhosa endotoxin or saline. There were no significant increases in DC myelopoiesis, but significant increases in host animal total tibial proliferative granulocytes on day 4 and suggestive increases in nonproliferative granulocytes on day 7 of DC culture. Further studies utilizing progressively increasing doses of intravenous endotoxin in irradiated or normal host mice implanted with DC with normal marrow showed: (1) a lack of correlation of serum CSA or inhibitor level with DC myelopoiesis; (2) elevations of CSA levels within DC relative to serum levels in all groups; and (3) a general inverse correlation of DC myelopoiesis with marrow cellularity.