Studies of hematopoietic stem cells spared by 5-fluorouracil.
Open Access
- 1 March 1984
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 159 (3), 679-690
- https://doi.org/10.1084/jem.159.3.679
Abstract
Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. 'Older' stem cells with a longer mitotic history are, according to the hypothesis, more likely to differentiate. 5-fluorouracil may be toxic to the older stem cells and selectively spare the more primitive subpopulation. Although the surviving cells may not themselves be able to form spleen colonies, they may give rise to an older cohort of cells more likely to differentiate and form spleen colonies. It is the requisite developmental maturation within the stem cell compartment that may be responsible for the delay in appearance of spleen colonies derived from FU-treated marrow. Our results support this explanation and identify the locus of at least part of this activity as the bone marrow. We found that the FU-treated marrow did not cause an increase in spleen colony numbers between 8 and 14 d in hosts with a long-standing marrow aplasia, due to the incorporation of 89Sr into bone. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation.Keywords
This publication has 19 references indexed in Scilit:
- Long-term erythropoietic repopulating ability of old, young, and fetal stem cells.The Journal of Experimental Medicine, 1983
- Partitioning of bone marrow into stem cell regulatory domains.Proceedings of the National Academy of Sciences of the United States of America, 1982
- Serial depletion and regeneration of the murine hematopoietic system. Implications for hematopoietic organization and the study of cellular agingThe Journal of Experimental Medicine, 1982
- Haemopoietic stem cells: possibility of toxic effects of 5-fluorouracil on spleen colony formation.1981
- Self‐maintenance capacity of CFU‐SJournal of Cellular Physiology, 1980
- Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell?Nature, 1979
- Competition between erythropoietin and colony-stimulating factor for target cells in mouse marrow.1979
- Effect of erythropoietin on regeneration of hematopoietic stem cells after 5-fluorouracil administration.1969
- Hemopoietic spleen colony studiesDevelopmental Biology, 1967
- Decline in colony‐forming ability of marrow cells subjected to serial transplantation into irradiated miceJournal of Cellular and Comparative Physiology, 1964