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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3781-3790
Lymphoid-Restricted Development From Multipotent Candidate Murine Stem
Cells: Distinct and Complimentary Functions of the c-kit and
flt3-Ligands
Ole Johan Borge,
Jörgen Adolfsson, and
Annica Mårtensson,
Inga-Lill Mårtensson, and Sten E.W. Jacobsen
From the Stem Cell Laboratory, the Department of Molecular Medicine
and Gene Therapy, the Department of Internal Medicine, Institute for
Laboratory Medicine, University Hospital of Lund, Lund, Sweden; The
Scripps Research Institute, La Jolla, CA; and Developmental Immunology,
The Babraham Institute, Babraham, Cambridge, UK.
The two tyrosine kinase receptors, c-kit and flt3, and their
respective ligands KL and FL, have been demonstrated to play key and
nonredundant roles in regulating the earliest events in hematopoiesis.
However, their precise roles and potential interactions in promoting
early lymphoid commitment and development remain unclear. Here we show
that most if not all murine
Lin /loSca1+c-kit+ bone
marrow (BM) cells generating B220+CD19+
proB-cells in response to FL and interleukin-7 (IL-7) also have a
myeloid potential. In contrast to FL + IL-7, KL + IL-7 could not
promote proB-cell formation from
Lin/loSca1+c-kit+ cells.
However, KL potently enhanced FL + IL-7-stimulated proB-cell formation, in part through enhanced recruitment of FL + IL-7-unresponsive Lin/loSca1+c-kit+
progenitors, and in part by enhancing the growth of proB-cells. The
enhanced recruitment (4-fold) in response to KL occurred exclusively from the
Lin/loSca1+c-kit+flt3
long-term repopulating stem cell population, whereas KL had no effect
on FL + IL-7-stimulated recruitment of
Lin/loSca1+c-kit+flt3+
short-term repopulating cells. The progeny of FL + IL-7-stimulated Lin/loSca1+c-kit+ cells
lacked in vitro and in vivo myeloid potential, but efficiently reconstituted both B and T lymphopoiesis. In agreement with this FL,
but not KL, efficiently induced expression of B220 and IL-7 receptor- on
Lin/loSca1+c-kit+flt3+
cells. Thus, whereas KL appears crucial for recruitment of FL + IL-7-unresponsive candidate (c-kit+flt3)
murine stem cells, FL is essential and sufficient for development toward lymphoid restricted progenitors from a population of
(c-kit+flt3+) multipotent short-term
reconstituting progenitors.
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