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Erythropoietin is both a mitogen and a survival factor
JL Spivak, T Pham, M Isaacs and WD Hankins
Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD.
Erythropoietin (Ep) regulates the proliferation and differentiation of
erythroid progenitor cells, but whether it functions solely as a survival
factor or also acts as a mitogen is unresolved. Because late erythroid
progenitor cells (CFU-E) are largely in cell cycle, we examined this issue
by using an Ep-dependent, murine erythroleukemia cell line, HCD-57. In the
presence of human Ep and fetal calf serum, HCD-57 cells had a doubling time
of approximately 24 hours, and during log-phase growth approximately 36% of
the cells were in G1, 45% in S, and 19% in G2/M. With Ep deprivation, there
was a gradual loss of viability and an arrest of proliferation with a 44%
increase in the G0/G1 population, which could be reversed by reexposure to
Ep even after 72 hours of hormone withdrawal. As little as 2 hours of
exposure to Ep was sufficient to stimulate DNA synthesis, and the lag time
for initiation of DNA synthesis after exposure to the hormone was
approximately 10 hours as measured by either incorporation of labeled
thymidine into DNA or cell cycle analysis by flow cytometry. RNA synthesis,
by contrast, was initiated within 2 hours after exposure to Ep and did not
require DNA synthesis. Total cell DNA content increased after exposure to
Ep, indicating that it was acting as mitogen in HCD- 57 cells. Ep was also
able to stimulate DNA synthesis in the absence of serum as well as in its
presence, indicating that the hormone could act as both a competence and a
progression factor. Qualitative analysis of the integrity of HCD-57 DNA by
electrophoresis in agar as well as direct measurement of DNA fragmentation
after metabolic labeling with radioactive thymidine indicated that
programmed cell death was occurring that could be reduced but not
completely prevented by Ep. These data indicate that Ep acts as both a
mitogen and a survival factor for HCD-57 cells.
Volume 77,
Issue 6,
pp. 1228-1233,
03/15/1991
Copyright © 1991 by The American Society of Hematology
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