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Rapid and sustained hematopoietic recovery in lethally irradiated mice
transplanted with purified Thy-1.1lo Lin-Sca-1+ hematopoietic stem cells
N Uchida, HL Aguila, WH Fleming, L Jerabek and IL Weissman
Department of Pathology, Stanford University School of Medicine, CA 94305.
Hematopoietic stem cells (HSCs) are believed to play a critical role in the
sustained repopulation of all blood cells after bone marrow transplantation
(BMT). However, understanding the role of HSCs versus other hematopoietic
cells in the quantitative reconstitution of various blood cell types has
awaited methods to isolate HSCs. A candidate population of mouse HSCs,
Thy-1.1lo Lin-Sca-1+ cells, was isolated several years ago and, recently,
this population has been shown to be the only population of BM cells that
contains HSCs in C57BL/Ka-Thy-1.1 mice. As few as 100 of these cells can
radioprotect 95% to 100% of irradiated mice, resulting long-term
multilineage reconstitution. In this study, we examined the reconstitution
potential of irradiated mice transplanted with purified Thy-1.1lo
Lin-Sca-1+ BM cells. Donor-derived peripheral blood (PB) white blood cells
were detected as early as day 9 or 10 when 100 to 1,000 Thy-1.1lo
Lin-Sca-1+ cells were used, with minor dose-dependent differences. The
reappearance of platelets by day 14 and thereafter was also seen at all HSC
doses (100 to 1,000 cells), with a slight dose-dependence. All studied HSC
doses also allowed RBC levels to recover, although at the 100 cell dose a
delay in hematocrit recovery was observed at day 14. When irradiated mice
were transplanted with 500 Thy-1.1lo Lin-Sca-1+ cells compared with 1 x
10(6) BM cells (the equivalent amount of cells that contain 500 Thy-1.1lo
Lin-Sca-1+ cells as well as progenitor and mature cells), very little
difference in the kinetics of recovery of PB, white blood cells, platelets,
and hematocrit was observed. Surprisingly, even when 200 Thy1.1lo Lin-Sca-
1+ cells were mixed with 4 x 10(5) Sca-1- BM cells in a competitive
repopulation assay, most of the early (days 11 and 14) PB myeloid cells
were derived from the HSC genotype, indicating the superiority of the
Thy-1.1lo Lin-Sca-1+ cells over Sca-1- cells even in the early phases of
myeloid reconstitution. Within the Thy-1.1lo Lin-Sca-1+ population, the
Rhodamine 123 (Rh123)hi subset dominates in PB myeloid reconstitution at 10
to 14 days, only to be overtaken by the Rh123lo subset at 3 weeks and
thereafter. These findings indicate that HSCs can account for the early
phase of hematopoietic recovery, as well as sustained hematopoiesis, and
raise questions about the role of non-HSC BM populations in the setting of
BMT.
Volume 83,
Issue 12,
pp. 3758-3779,
06/15/1994
Copyright © 1994 by The American Society of Hematology
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