Physiology of erythropoietin during mammalian development
Authors: Halvorsen S , Bechensteen AG 
Published: August 2010

Growth is a fundamental process of mammalian development. Several observations regarding regulation of erythropoiesis during growth are not easily explained by the hypoxia‐erythropoietin (Epo) concept. This review focuses primarily on this aspect of the physiology of Epo. The question is raised of whether this regulation during growth is based on the hypoxia‐Epo mechanism alone, or whether Epo acts in concert with general growth‐promoting factors, particularly growth hormone (GH) and the insulin‐like growth factors (IGF‐I and ‐II). Supporting the latter hypothesis is the observation that the Epo and GH/IGF systems are activated by hypoxia and share similar receptors and pathways. Recent studies indicate that human fetal and infant growth is stimulated by GH, IGF‐I and IGF‐II. Epo, GH and IGFs are expressed early in fetal life. Although the rate of erythropoiesis in the fetus is high, serum Epo levels are low. The Epo response to hypoxia in the fetus and neonate is reduced compared with adults. Following delivery the Epo levels vary between species, probably related to the oxygen transport capacity of the hemoglobin (Hb) mass. IGF‐I levels are low in the fetus and increase slowly following birth, except in preterm infants in whom the levels decline. In all mammals Hb declines following birth, giving rise to “early anemia”. Except in the human, Epo levels increase proportionally with the fall in Hb, but there is a discrepancy between the curves for serum immunoreactive Epo (siEpo) and for erythropoiesis stimulating factors (ESF): the latter include other stimulatory factors in addition to Epo. Hypertransfusion of mice in the period of “early anemia” suppresses siEpo, but not ESF and erythropoiesis, as it does in adult mice. GH and IGF‐I have direct effects on erythropoiesisin vitroand act particularly at the later stages of red cell differentiation. IGF‐I acts synergistically with Epo, and its effects are most marked when Epo levels are low. Human recombinant (rhu) IGF‐I stimulates erythropoiesis in neonatal rats, but not in newborn mice and lambs. In adult mice, in hypophysectomized rats and in mice with end‐stage renal failure, however, a stimulatory effect of this growth factor was found on red cell production. RhuGH stimulates erythropoiesis in GH‐deficient short children.

Conclusion: Fetal and early postnatal erythropoiesis are dependent on factors in addition to Epo. The likely candidates are GH and IGF‐I. Thein vitrostimulating effects of these factors on erythropoiesis are convincing, but more data are needed on thein vivoeffects.

The primitive erythropoiesis in the yolk sac is Epo independent, while the definitive erythropoiesis in the fetal liver and later in the bone marrow and throughout life is Epo dependent. The hypoxia‐Epo response functions from early gestation, at least from the 20th week in the human, during the perinatal period and during the “early anemia” connected with the early growth period and reaching into adult age. The degree of anemia in the fetus must be more pronounced to increase Epo levels than in the adult mammal, and newborn mammals have a reduced Epo plasma response to hypoxia. Serum Epo levels are moderately elevated in cord blood from human infants. Such data are lacking in other mammals, but in blood sampled shortly after birth the levels were elevated in some species (mice, rats) while undetectable in others (lambs, piglets).

During the postnatal rapid growth all mammals studied develop low Hb, termed “early anemia”. The “early anemia” is iron responsive in all non‐human mammals tested, and either the anemia is alleviated (pigs, mice, rabbits) or Hb is significantly increased (rats) by parenteral iron supplementation. The Epo levels are low during the physiological anemia of term infants, whereas they increase markedly during the “early anemia” of other mammals. In iron‐treated, non‐anemic young mice the siEpo levels are equal to levels in adults, while ESF levels are elevated in similarly treated rabbits. Great variations exist in both Hb and Epo levels within the same species in different studies and the results are sometimes contradictory. A possible reason for this is the varying rearing conditions and nutrition, particularly iron intake or supplements. In future studies, the rearing conditions and nutrition should be specified.

Several data indicate that both fetal and postnatal erythropoiesis during growth is dependent on other factors in addition to Epo. GH and IGF‐I are likely candidates, probably working synergistically with Epo. IGF‐I has a direct effect on erythropoiesis in cultures and its effects are most prominent when Epo levels are low.In vivostudies have not convincingly confirmed thein vitroeffects in young animals, but have done so in normal adult mice, in mice with renal failure and in hypophysectomized rats. More studies are needed on the regulation of erythropoiesis and the possible synergism between Epo and general growth factors (GH and/or IGF‐I) in young growing animals. It is essential that such studies be designed with due consideration given to the knowledge of “early anemia” and the great variations in basic hematological variables in this age period.