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The Journal of
The American Society of Hematology
BLOOD
VOL 81, NO 10
MAY 15, 1993
EDITORIAL
Competitive Repopulation in Unirradiated Normal Recipients
By David E. Harrison
0
FTEN IN SCIENCE conventional wisdom develops
from ideas that gain wide acceptance without definitive proof. Such paradigms often prove to be misleading,
and block potentially important avenues of research. One
such idea may be that primitive hematopoietic stem cells
(hereafter called stem cells) function in close association
with a supporting matrix, a microenvironmental niche.
This close association is thought to bestow a competitive
advantage on stem cells already in residence, so that such
cells must be removed or defective before donor stem cells
can be successfully transplanted.
The article by Quesenberryet all in this issue of Bloodon
transplantationinto recipients with undamaged stem cells
confirmsand extends previous pioneering w0rk.2,~
In the most
impressive experiment, recipients received marrow from 2
tibias and 2 femurs daily for 5 days; after 12 months, the
mean percentages of donor cells in marrow, spleen, and thymus were 48%, 32%, and 29%, respectively. Thus, a high
dose of donor marrow can successfully and permanently repopulate a recipient without need for removing or damaging
recipient stem cells.
These results can be analyzed as competitive repopulation,
in which donor cells compete with cells in residence to repopulate the recipient. If 2 tibias and 2 femurs contain about
50 million cells, the 5 injections contain 250 million. The
recipient contains about 300 million marrow cells; thus, if
there is no competitive disadvantage for the donor cells, then
the expected percentage of donor cells is 250 divided by 250
plus 300, or 45%.As noted above, the results actually observed
are 48%, 32%, and 29%, suggesting that resident cells have
little or no advantage.
The high repopulating ability observed, which was almost that of the recipient’s own marrow, is surprising, because studies of previously transplanted marrow cells predict a substantial competitive disadvantage for the donor
cells resulting from deleterious effects of transplantation.
For example, marrow from recipients repopulated 4
months previously with 10 million marrow cells had about
one-ninth the repopulating ability of fresh m a r r ~ wThe
.~
damage may result from the rapid proliferation stimulated
to repopulate lethally irradiated recipients. In the current
experiment, there is no recipient cell loss and no abnormal
stimuli.
Blood, V o l 8 1, No 10 (May 15). 1993: pp 2473-2474
A potential problem with these studies is the wide variability between recipients. This does not fit previous findings that variability between recipients of mixtures of distinguishable marrow cells is inversely proportional to the
numbers of cells i n j e ~ t e d .It
~ .is~ possible that the use of
male donors in female recipients stimulated immune responses against the male antigen; differing degrees of immune responses resulting by chance could have increased
variabilities.
These results definitively. contradict the conventional
wisdom that recipient cells must be removed to leave space
for donor cells in the stem cell supporting microenvironmental “niches.” It is possible that stem cells need no special supporting niche. If this is true, stem cell proliferation
can be stimulated in vitro once the appropriate medium
is defined.
Of course, there are other possibilities. Stem cells may
require niches, but they may be dynamic, so cells already
occupying niches have no advantage over injected cells,
or there may be a large number of empty niches available
for injected cells. Finally, transplanted marrow may include the cells needed to form niches; these cells may be
damaged by 5-FU, thus explaining the poorer repopulation
found in that case.
These results also have direct implications for clinical
procedures in which it is desirable to transplant stem cells
without irradiation or drug treatment of the recipient.
The most prominent example is gene transplantation
using stem cells as vehicles. Such procedures apparently
will not be limited by the need to remove recipient stem
cells.
REFERENCES
1. Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenbeny PJ: Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood
81:2566, 1993
From The Jackson Laboratory, Bar Harbor, ME.
Address reprint requests to David E. Harrison, PhD, The Jackson
Laboratory, 600 Main St, Bar Harbor, ME 04609.
0 1993 by The American Society of Hematology.
0006-4971/93/8110-0048$3.00/0
2473
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
2474
2. Brecher G, Ansel JD, Micklem HS, Tjio JH, Cronkite EP: Special proliferative sites are not needed for seeding and proliferation of
transfused bone marrow cells in normal syngeneic mice. Proc Natl
Acad Sci USA 795085, 1982
3. Saxe DF, Boggs SS, Boggs DR: Transplantation of chromosomally marked syngeneic marrow cells into mice not subjected to hematopoietic stem cell depletion. Exp Hematol I2:277,
1984
4. Harrison DE, Stone M, Astle CM: Effects of transplantation
DAVID E. HARRISON
on the primitive immunohematopoietic stem cell (PSC). J Exp Med
172:431, 1990
5. Hamson DE, Astle CM, Lerner C Number and continuous
proliferative pattern of transplanted primitive immunohemopoietic
stem cells. Proc Natl Acad Sci USA 85:822, 1988
6. Hamson DE, Jordan CT, Zhong RK, Astle CM: Primitive hemopoietic stem cells: Direct assay of most productive populations
by competitive repopulation with simple binomial, correlation, and
covariance calculations. Exp Hematol 2 1:206, 1993
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1993 81: 2473-2474
Competitive repopulation in unirradiated normal recipients [editorial;
comment]
DE Harrison
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