Hb Switching in neonatal cultures. Increase of Hb A synthesis in presence of an erythroid potentiating activity (EPA)

Testa, Ugo; Vainchenker, William; Guerrasio, Angelo; Beuzard, Yves; Breton-Gorius, J; Rosa, J.; Lusis, Aldons J.; Golde, David W.

doi:10.1002/jcp.1041100214

Cited by 4 publications

(1 citation statement)

References 39 publications

(30 reference statements)

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“…Previous attempts to identify factors that induce Hb F-to-Hb A switching have been unrewarding. No changes in globin chain synthesis have been noted when various types of conditioned media were used in culture (6), and contradictory information has been obtained on the effects of Hb F synthesis of the erythropoietic activity known as burst-promoting activity (12,13). It is noteworthy that our control cultures were grown in the presence of fetal calfserum.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Papayannopoulou¹,

Kurachi²,

Nakamoto³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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An erythropoietic activity that exerts a profound effect on fetal Hb synthesis is present in fetal sheep sera and it attains a peak concentration at the end ofthe second to the middle ofthe third trimester offetal life. The activity consistently inhibits the increased synthesis of fetal Hb in cultures of burst-forming units (BFUes) from normal adults. In cultures of BFUes from homozygous fi+-thalassemias the activity produces a striking decline in ychain synthesis, a decline in Gy/Ay chain synthesis ratio, and an increase in 6/y and a/non-a ratios-i.e., findings suggesting a genuine -to-P8 switch. The activity accelerates Hb F-toHb A switching in neonatal BFUe cultures but it has no effect on fetal Hb synthesis in cultures of BFUe obtained from human fetuses. These findings provide direct evidence that (a) humoral factors play a role in the regulation of the switch from fetal to adult Hb formation, and (b) progenitor cells from various stages of ontogeny respond differently to these factors. The results are compatible with the hypothesis that Hb switching during development is mediated through a change in a developmental program which controls the responsiveness of progenitor cells to "switching" activities in their environment.tial humoral inducers of Hb switching appear in sheep fetuses before or at the time Hb switching starts. We found that sera obtained from the ontogenetic time preceding the Hb switching in sheep have a profound effect on Hb F synthesis in human adult BFUe cultures. They influence Hb F-to-Hb A switching in neonatal BFUe cultures but have no effect on fetal BFUes.These results suggest that factors in the hemopoietic environment play a role in the switching process. Our findings further show that the response of hemopoietic cells to these environmental factors depends on the stage of ontogeny from which the cells derive. The simplest interpretation of these observations is that the cellular regulation of Hb switching is mediated through qualitative changes that occur in progenitor cells; as development progresses, the progenitor cells may acquire the ability to interact with activities present in their environment and this interaction either directly or indirectly (through changes in progenitor cell differentiative programs) brings about a switch of the program of globin synthesis in the erythroid cells. (1, 5, 7). We tested whether poten- METHODSThe cells used for culture were from peripheral blood or bone marrow ofadult volunteers, from umbilical cord bloods of neonates, and from livers or fetal blood of abortuses. Peripheral blood mononuclear cells were isolated through Ficoll-sodium Metrizoate (Lymphoprep, Nyegaard, Norway) centrifugation (1). Bone marrow cells were obtained from buffy coat preparations. Fetal liver cells were prepared as a single-cell suspension from liver fragments after removal of cell aggregates and stromal pieces (5). Appropriate cell concentrations (1-3 X 105/ ml) were cultured in methylcellulose plates in the presence of erythropoietin (2 international u...

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Section: Discussionmentioning

confidence: 99%

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Papayannopoulou¹,

Kurachi²,

Nakamoto³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Prostaglandin E2 mediated effects on the synthesis of fetal and adult hemoglobin in blood erythroid bursts

Datta

1985

Prostaglandins

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Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

Miller¹,

Perrine

Antognetti

et al. 1987

Blood

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Interferons have the ability to enhance or diminish the expression of specific genes and have been shown to affect the proliferation of certain cells. Here, the effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose- dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma- interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma- interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL- 2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes. This supports the concept that developmental globin gene switching can be regulated by environmental factors.

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Hb Switching in neonatal cultures. Increase of Hb A synthesis in presence of an erythroid potentiating activity (EPA)

Cited by 4 publications

References 39 publications

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Prostaglandin E2 mediated effects on the synthesis of fetal and adult hemoglobin in blood erythroid bursts

Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

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