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Survival or death of individual proerythroblasts results from differing
erythropoietin sensitivities: a mechanism for controlled rates of
erythrocyte production
LL Kelley, MJ Koury, MC Bondurant, ST Koury, ST Sawyer and A Wickrema
Division of Hematology, Vanderbilt University School of Medicine,
Nashville, TN 37232-2287.
Murine erythroid progenitors infected with the anemia-inducing strain of
Friend virus (FVA cells) undergo apoptosis when deprived of erythropoietin
(EPO). When cultured with EPO, they survive and complete terminal
differentiation. Although cell volume is decreased and nuclear chromatin is
condensed during both apoptosis and terminal differentiation, morphologic
and biochemical distinctions between these two processes were observed. In
apoptosis, homogeneous nuclear condensation with nuclear envelope loss
occurred in cells that had not reached the stage of hemoglobin synthesis.
In terminal erythroid differentiation, nuclear condensation with
heterochromatin, euchromatin, and nuclear envelope preservation occurred
simultaneously with hemoglobin synthesis. Cells with apoptotic morphology
appeared asynchronously in EPO-deprived cultures, indicating that only a
portion of the cells were undergoing apoptosis at any given time. The
percentages of apoptotic cells and cleaved DNA increased with time in
EPO-deprived cultures. Inhibition of DNA cleavage was directly proportional
to EPO concentration over a wide physiologic range, demonstrating a
heterogeneity in susceptibility to apoptosis based on variability in the
EPO sensitivity of individual cells. A subpopulation of FVA cells with
increased EPO sensitivity (decreased EPO requirement) was isolated from
EPO-deprived cultures. This increased EPO sensitivity did not result from
differences in EPO receptor number, affinity, or structure, suggesting that
the differences are in the signal transduction pathway. These results
indicate that control of red blood cell production involves both prevention
of apoptosis by EPO and heterogeneity in the EPO requirement of individual
progenitor cells.
Volume 82,
Issue 8,
pp. 2340-2352,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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