Hemopoietic stem cells: An analytic review of hemopoiesis

Current knowledge and concepts about stem cells are reviewed. The best morphologic candidate today is a small nonlymphocytic bone marrow cell in mouse and monkey. Methods for concentration and separation of pluripotent and committed stem cells in mouse and monkey are well advanced. There is a common committed stem cell for granulocytes and macrophages. Tissue microenvironment and cell-cell interaction play important roles in determining the direction of differentiation of pluripotent stem cells in vivo. These factors are not required for in vitro growth and differentiation or in vivo growth in diffusion chambers. The CSF is produced by the monocyte-macrophage family of cells as well as other tissues. CSF is not produced by granulocytes. The latter, in fact, appear to inhibit granulopoiesis. An in vivo effect of CSF has not yet been convincingly demonstrated. Erythropoietin acts by initiating hemoglobin synthesis at CSC level and accelerating its synthesis in the differentiated erythropoietic compartments. Hypoxia produces respiratory alkalosis leading to an increased erythrocyte oxygen affinity Ep secretion followed by an increase in 2,3 DPG in erythrocytes and an increased flow of oxygen to tissues. Pluripotent and committed stem cells migrate through the blood. The daily blood turnover rate is equal to estimated pool of PHSC in the marrow. Presumably, the PHSC and the CSC are in dynamic exchange between the blood and blood-forming tissues. There is growing evidence that thymic cells exert a stimulatory effect on regeneration of injured PHSC and may in fact be related to normal steady-state kinetics. Hypoxia, bleeding, radiation, chemotherapeutic agents, and endotoxin direct an increased fraction of PHSC and CFU-C into DNA synthesis, thus increasing the number of cells produced per cell present. Whether absolute production increases depends on the total number of PHSC in S. Several lines of evidence now suggest the existence of a fast intramedullary feedback loop by which the PHSC senses depletion of the differentiated compartments and directs PHSC to differentiate, thus initially depleting the PHSC, which then shifts gears and produces more cells by the remaining cells going into S. A kinetic model of human PHSC and CSC is proposed based on known erythrocyte cell and granulocyte turnover rates and the structure of human marrow. This model states that in vitro assays for CSC grossly underestimate their abundance in the marrow. The frequency of mitosis was calculated based on the foregoing model, and it was suggested that human stem cells can divide many more times than human fibroblasts in culture.