Roles of erythropoietin, insulin-like growth factor 1, and unidentified serum factors in promoting maturation of purified murine erythroid colony-forming units

Abstract

We have used 75% to 90% pure murine erythroid colony-forming units (CFU- E) to delineate the processes and factors underlying their maturation. These CFU-E form 32 cell colonies and are drawn from what we term generation I of a six-generation long maturation sequence (Landschulz et al, Blood 79:2749, 1992). Applying assays of 59Fe-heme biosynthesis and colony numbers as measures of maturation and analyses of DNA degradation as an index of programmed cell death, we find that (1) erythropoietin (Epo) enhances maturation throughout most of its course; (2) Epo first seems able to forestall DNA degradation when CFU-E reach generation II; (3) the processes that Epo elicits thereafter start to persist when Epo is withdrawn; (4) insulin-like growth factor I (IGF-I) also forestalls DNA breakdown, but later loses effectiveness; (5) IGF-I adds little to maturation when Epo levels are high, but when Epo levels are low, enhances it substantially; and (6) for maturation to be entirely optimal, an unidentified serum factor(s) is probably required when Epo levels are high and is certainly needed when Epo levels are like those in normal animals. Quantitatively, about 40% of optimal in vitro erythropoiesis at normal Epo levels depends on Epo alone, another 30% or less on the addition of IGF-I, and the remaining 30% or more on the addition of unidentified serum factor(s). Applied together, these three or more factors lead to two-thirds of the maximum maturation realized with saturating Epo levels. Because we also find that heme accumulated in CFU-E culture can closely approach levels in red blood cells, we suppose that our conclusions apply as well to CFU-E maturation in vivo.

Increase in haemoglobin concentrations in growth hormone deficient adults during human recombinant growth hormone replacement therapy

“…There also might be a functional relationship between members of the cytokine receptor superfamily as Bazan (1990) suggested. Together with stem cell factor, Epo controls the proliferation of erythroid progenitors (Boyer et al, 1992). Similar positive effects of IGF-I on erythropoiesis were demonstrated in vivo in animal studies (Kurtz et al, 1990;Tsarfaty et al, 1994).…”

“…In several reports it has been demonstrated that insulin-like growth factor-I (IGF-I) has stimulatory actions on granulopoiesis in animals (Fu et al, 1991;Wiedermann et al, 1991;Arkins et al, 1993) and erythropoiesis in vitro and in vivo (Kurtz et al, 1988;Merchav et al, 1988;Kurtz et al, 1990;Correa & Axelrad, 1991;Dainiak et al, 1991;Boyer et al, 1992;Merchav et al, 1992;Muta & Krantz, 1993;Sanders et al, 1993;Bechensteen et al, 1994;Muta et al, 1994;Tsarfaty et al, 1994). Administration of human recombinant growth hormone (rhGH) is known to increase serum IGF-I concentration (Salomon et al, 1989;Binnerts et al, 1992b;Moller et al, 1993).…”

Physiology of erythropoietin during mammalian development

“…Their ndings indicate that IGF has an Epo-like activity, providing strong evidence for the existence of an Epo-independent pathway for normal human adult erythropoiesis, possibly operative when Epo levels are low. Boyer et al (49) found that the relative effect of IGF-I was strongest in the absence of Epo, con rming the observation that the IGF-I effect was less evident when Epo levels were high. IGF-I receptors have been found on reticulocytes from rats and on erythrocytes from humans (50).…”

Erythropoietin-independent erythrocyte production: signals through gp130 and c-kit dramatically promote erythropoiesis from human CD34+ cells.

“…EPO has been shown as the principal factor that controls proliferation, differentiation, and apoptosis of human erythroid progenitor cells through its special cell surface receptor (EPOR) signaling. Several cytokines such as SCF, IL-3, GM-CSF, IGF-1, and hepatocyte growth factor (HGF) were reported to enhance the proliferation and/or maturation of erythroid progenitors in vitro, but failed to do so without EPO, suggesting the central role of EPO in erythropoiesis (21)(22)(23)(24)(25)(26)(27)(28). No factor so far has been reported to possess activity similar to that of EPO, especially on relatively late stage erythroid progenitors.…”