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Identification of properties that can distinguish primitive populations of
stromal-cell-responsive lympho-myeloid cells from cells that are
stromal-cell-responsive but lymphoid-restricted and cells that have
lympho-myeloid potential but are also capable of competitively repopulating
myeloablated recipients
ME Lemieux and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
We have recently described a modification of the long-term culture-
initiating cell (LTC-IC) assay that allows the identification and
quantitation of a subset of murine LTC-IC that are able to generate both
myeloid and lymphoid progeny in vitro. These "LTC-ICML" are inseparable
from either standard LTC-IC or cells with long-term in vivo lympho-myeloid
repopulating potential (competitive repopulating units, or CRU) present in
normal adult mouse marrow but are detected at 15- to 30-fold lower
frequencies. To determine whether at least part of this discrepancy is due
to a reduced sensitivity of the LTC-ICML assay, a number of strategies to
try to improve the original protocol were tested. Prolongation of the
second phase of the assay (when the cells are maintained under lymphoid LTC
conditions) from 7 to 10 days and inclusion of Flt3 ligand (FL) in the
assay used to detect the production of B-lineage cells (CFU-pre-B)
increased the average yield of CFU-pre-B per LTC-ICML by a factor of 3- to
20-fold; however, neither of these manipulations increased the frequency of
LTC-ICML detected. Similarly, the use of S17 fibroblasts as feeders also
did not improve the sensitivity of the LTC-ICML assay. On the other hand,
approximately threefold more LTC-ICML could be detected when the initial
phase of the assay (when the cells are maintained under myeloid LTC
conditions) was shortened from 4 weeks to 1 week. In addition, this latter
modification showed the existence in adult mouse marrow of a previously
unrecognized, very early B220- stage of lymphoid development characterized
by a relative resistance to both 5-fluorouracil and hydrocortisone. The
discovery of such cells is of significant interest; however, their presence
in adult mouse marrow in numbers comparable to those of both LTC-ICML and
myeloid-restricted LTC-IC imposes severe restrictions on the use of the
shorter LTC-ICML assay which offset its increased sensitivity.
Interestingly, the present studies also show that both LTC-IC and LTC-ICML
numbers are significantly better maintained (approximately twofold to
sixfold) in myeloid LTC than are CRU. This differential maintenance of
LTC-IC and CRU in vitro may be related to the fact that the detection of
each of these two functionally defined progenitors involves the use of
different ligand receptor systems. Alternatively, it is possible that at
least some LTC- IC and CRU may represent developmentally distinct cell
types. Taken together, these findings suggest a model of hematopoietic stem
cell regulation in which retention of totipotentiality and maintenance of
responsiveness to specific regulators may not be tightly linked.
Volume 88,
Issue 5,
pp. 1639-1648,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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