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Long-term repopulation of irradiated mice with limiting numbers of purified
hematopoietic stem cells: in vivo expansion of stem cell phenotype but not
function
GJ Spangrude, DM Brooks and DB Tumas
Rocky Mountain Laboratories, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Hamilton, MT.
Hematopoietic stem cells were isolated from normal adult mouse bone marrow
based on surface antigen expression (Thy-1.1(low)Lin(neg)Ly- 6A/E+) and
further selected for low retention of rhodamine 123. This population of
cells (Rh-123low) could mediate radioprotection and long- term (greater
than 12 months) repopulation after transplantation of as few as 25 cells.
Transfer of five genetically marked Rh-123low cells in the presence of
10(5) normal bone marrow cells resulted in reconstitution of peripheral
blood by greater than 10% donor cells in 64% (30 of 47) of recipient mice.
Of 46 animals surviving after 24 weeks, 10 had over 50% donor-derived cells
in peripheral blood. Two general patterns of long-term reconstitution were
observed: one in which many donor-derived cells were observed 5 to 6 weeks
after reconstitution and another in which donor-derived cells were rare
initially but expanded with time. This result suggests that two classes of
long-term repopulating hematopoietic stem cells exist, differing in their
ability to function early in the course of transplantation. Alternatively,
distinct anatomic sites of engraftment may dictate these two outcomes from
a single type of cell. As an approach to measure the extent of self-renewal
by the injected cells, recipients of five or 200 stem cells were killed 8
to 13 months after the transplants, and Thy- 1.1(low)Lin(neg)Ly-6A/E+
progeny of the original injected cells were isolated for a second
transplant. While a numerical expansion of cells expressing the cell
surface phenotype of stem cells was observed, along with activity in the
colony-forming unit-spleen assay, the expanded cells were vastly inferior
in radioprotection and long-term reconstitution assays when compared with
cells freshly isolated from normal animals. This result demonstrates that
in stem cell expansion experiments, cell surface antigen expression is not
an appropriate indicator of stem cell function.
Volume 85,
Issue 4,
pp. 1006-1016,
02/15/1995
Copyright © 1995 by The American Society of Hematology
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