Stem Cell Factor

Jonathan Roy Keller1,* and Diana Marie Linnekin2

1
Intramural Research and Support Program-SAIC, Frederick Cancer Research and
Development Center-NCI, Building 560, Room 12-03, PO Box B, Frederick, MD 21702-1201, USA
2
Basic Research Laboratory-DBS, Frederick Cancer Research and Development Center-NCI,
Building 567, PO Box B, Frederick, MD 21702-1201, USA
* corresponding author tel: 301-846-1461, fax: 301-846-6646, e-mail: kellerj@mail.ncifcrf.gov
DOI: 10.1006/rwcy.2000.09003.

SUMMARY stromal cells (macrophages, fibroblasts, endothelial

Stem cell factor (SCF) and its receptor, c-Kit, are
essential for hematopoietic, melanocyte, and germ cell
development. In the hematopoietic compartment, SCF
has been shown to act on cells at multiple stages of
development, including effects on primitive stem cells
and their more differentiated progeny. In particular,
SCF can function to promote stem/progenitor cell
survival, proliferation and differentiation (especially
in combination with other growth factors), adhesion,
activation, and migration/chemoattraction. While c-
Kit is highly expressed on differentiated mast cells
and SCF is a potent mast cell growth factor, c-Kit
expression is downregulated during the maturation of
all other hematopoietic lineages. SCF can exist in
both soluble and membrane forms which may have
distinct biological functions in vivo. Further under-
standing of this important hematopoietic regulator
will provide important insights into the biology,
biochemistry, and molecular biology of hematopoetic
stem cells.
BACKGROUND
Discovery
Definitive hematopoiesis is a complex cellular process
that is regulated, in part, by hematopoietic growth
factors (HGFs) and the bone marrow microenviron-
ment, which act to promote the survival, prolifera-
tion, and differentiation of hematopoietic stem cells
and their progeny (Spangrude, 1991; Ogawa, 1993;
Metcalf, 1993). HGFs are produced by accessory or
cells, and adipocytes) in the bone marrow and else-
where, which interact with specific receptors
expressed on hematopoietic cells. The story of the dis-
covery of one HGF/receptor pair, stem cell factor
(SCF) and SCF receptor (SCFR), illustrates the
importance of HGFs in hematopoietic development.
This story began with studies of inbred mouse
strains that have naturally occurring mutations affect-
ing SCF or its receptor that were initiated 20 years
ago. Specifically, homozygote offspring from W mouse
strains (white spotting locus on chromosome 5), or Sl
mouse strains (steel locus on chromosome 10) showed
varying degrees of impaired hematopoietic develop-
ment (hypoplastic with macrocytic anemia), altera-
tions in coat color or pigmentation (lack of cutaneous
melanocytes), and defects in gametogenesis (sterility)
(Russell, 1979; Silvers, 1979). Bone marrow trans-
plantation and embryo fusion studies using W or Sl
mutant mouse strains led to the seminal observation
that the W mutant defects were intrinsic to hemato-
poietic stem and mast cells, while the Sl mutant
defects were extrinsic to hematopoietic cells in that
bone marrow stromal cells were required to support
hematopoietic development (Russell et al., 1959;
Altus et al., 1971; McCulloch et al., 1964, 1965).
Because both W and Sl mice showed defects in the
same three cell lineages (hematopoietic, melanocyte,
and germ cell) Elisabeth Russell speculated that the
W locus might encode a growth factor receptor and
the Sl locus its complementary ligand (Russell, 1979).
This hypothesis was confirmed, in part, by the
observation that the W locus encoded the proto-
oncogene c-kit (SCFR), a transmembrane tyrosine
kinase, which was largely deleted in one strain of W
mice (W/W) mice and results in the most severe
878 Jonathan Roy Keller and Diana Marie Linnekin
phenotype in homozygous offspring (prenatal letha-
lity). W mouse strains that produce viable homo-
zygous offspring do not show deleted SCFR, but
rather have mutations in the kinase domain that
affect the kinase enzymatic activity (Charbot et al.,
1988; Geissler et al., 1988). SCFR is structurally rela-
ted to other transmembrane tyrosine kinases, including
c-fms, the receptor for macrophage colony-stimulat-
ing factor (M-CSFR), and platelet-derived growth
factor receptor (PDGFR) (Qui et al., 1988).
The search for the SCFR ligand ended several years
later when three groups simultaneously purified it
from medium conditioned by fibroblasts (stromal
cells) or a rat liver-derived cell by assaying the pro-
liferative response of cell lines or normal bone
marrow cells to SCFR ligand (Huang et al., 1990;
Zsebo et al., 1990a; Williams et al., 1990). The proteins
were purified to homogeneity, sequenced and used
to clone the corresponding cDNAs (Anderson et al.,
1990; Copeland et al., 1990; Martin et al., 1990).
Alternative names
SCF is also known as steel factor (SF) because it was
mapped to the Sl locus, Kit ligand (KL), and mast
cell growth factor (MCGF) (Anderson et al., 1990;
Copeland et al., 1990; Huang et al., 1990; Martin et al.,
1990; Williams et al., 1990; Zsebo et al., 1990b).
Structure
SCF is produced in both soluble and transmembrane
forms that are encoded by two distinct mRNAs
generated from the same gene by alternate splicing of
the primary RNA transcript (Flannagan et al., 1991;
Anderson et al., 1990, 1991). Both isoforms of SCF
are initially produced as transmembrane proteins that
contain a 25 amino acid signal peptide sequence
(SCF248 or SCF220). Transmembrane SCF248 can be
proteolytically cleaved to give rise to soluble SCF,
which contains the first 164 amino acids of SCF248
(Figure 1). The alternatively spliced isoform, SCF220,
encodes a shorter 220 amino acid transmembrane
protein identical to SCF248 except that it lacks amino
acids 147±177, the region containing the proteolytic
cleavage site. Little or no soluble SCF is produced
from SCF220.
Main activities and
pathophysiological roles
SCF plays essential roles in the survival, growth, and
differentiation of cells responsible for hematopoietic,
Figure 1 Soluble and transmembrane forms of SCF.
The amino acid sequences encoded by exon 6 are
shown in light blue, which contains the major
proteolytic site (purple arrow) that results in the
production of soluble SCF164. Soluble SCF164 forms
nonconvalently linked dimers using the cysteine
residues indicated. SCF220 lacks exon 6 and the pri-
mary proteolytic site and remains membrane bound.
The signal peptide sequence is shown in purple and the
transmembrane domain is shown as a green box. (Full
colour figure can be viewed online.)
germ, and melanocyte cell development during both
embryonic development and adult life (Bernstein
et al., 1991b; Besmer et al., 1993). In particular, SCF
is expressed along the migratory pathways for pri-
mordial germ cells and melanocytes as well as sites of
active hematopoiesis (fetal liver). SCF is essential for
the migration and homing of stem cells to their appro-
priate developmental sites; moreover, SCF directly
promotes the survival of these stem cell populations
and greatly enhances their proliferation in response to
other growth factors. While SCF is critical for the
development of a number of tissues, this review will
only focus on hematopoietic cells and will refer to
cells from other tissue where appropriate.
GENE AND GENE REGULATION
Accession numbers
SCF cDNAs have been cloned and sequenced from
a variety of species including mouse (GenBank:
U44725) (Anderson et al., 1990; Huang et al., 1990;
Zsebo et al., 1990b), human (GenBank: M59964), rat
(GenBank: M59964) (Martin et al., 1990), pig (L07786)
(Zhang and Anthony, 1994), chicken (D13516) (Zhou
et al., 1993), quail (GenBank: U43079) (Pettite and
Kulik, 1996), dog (S53329) (Shull et al., 1992), cat
(Dunham and Onions, 1995) (DDBJ: D50833), and
horse (GenBank: AF053498).
 Stem Cell Factor 879

binding motif for the transcription factors TFIID and

Chromosome location SP1 (Bedell et al., 1996; Taylor et al., 1996; Jiang et al.,
1997). The human SCF promoter contains a TATA
Mouse SCF has been mapped to chromosome 10 in a
box beginning at ÿ38 bp and a CCAAT box at
region between the peptidase 2 (Pep-2) and phenylhy-
ÿ71 bp (Figure 2). The major transcription initiation
droxylase (Pah) genes. Comparing the maps of mouse
start site for SCF in mouse brain, lung, kidney, heart,
and human chromosomes indicated that the human
ovary, and testes is located 28 nucleotides down-
SCF gene might be located on the distal end of the
stream from the consensus TATA motif in the murine
long arm of human chromosome 12 (Copeland et al.,
promoter (Bedell et al., 1996). There are also three
1990; Huang et al., 1990; Zsebo et al., 1990b). This was
ATGs located at positions ‡88, ‡123, and ‡193,
later confirmed by in situ hybridization where it was
with the latter encoding the initiator methionine for
shown that human SCF mapped to chromosome
SCF, however; initiation of translation from ‡88 or
12q22 (Anderson et al., 1991) and somatic cell hybrids
‡123 would produce peptides of 37 and 7 amino acids
which mapped SCF to 12q14.3-qter (Geissler et al.,
in length respectively. Other important sites in the
1991).
human promoter include SP1 sites at ÿ224, ÿ139,
The mouse SCF gene spans roughly 50 kb and is
and ÿ50, AP-2 sites at ÿ202 and ÿ91, and AP-1 and
composed of nine exons (Martin et al., 1990; Brannan
cAMP-response elements further upstream. In com-
et al., 1992). The locations of the intron and exon
parison, the mouse promoter contains SP1 sites, a
boundaries are highly conserved between species
hepatocyte-acute phase factor 1 motif (H-APF-1), a
including human, rat, and mouse. The first exon of
negative regulatory element-box 1 (NRE-1), a reverse
the mouse encodes 198 nucleotides of the 50 UTR and
TPA responsive element (TGAGTA), TRE/Rev sites,
the first five amino acids of the signal peptide. Exons
NFB elements, as well as AP-2 and AP-1 sites
2±6 encode the extracellular domain of the transmem-
(Taylor et al., 1996; Jiang et al., 1997). A functional
brane-bound ligand, while exon 7 encodes a portion
analysis of the rat SCF promoter sequences per-
of the extracellular domain and 23 amino acids of the
formed by transfecting a reporter plasmid-containing
membrane-spanning region. Exons 8 and 9 encode 23
promoter sequences into SCF-expressing and non-
amino acids and 22 amino acids of the cytoplasmic
SCF-expressing cell lines showed that sequences from
domain, respectively.
ÿ119 to ‡43 nucleotides contained the SCF core
There are two major RNA transcripts for SCF
promoter activity (Jiang et al., 1997). Transfection of
detected by northern blot analysis that range in size
plasmids containing additional 50 sequence (up to
from 5.5 kb to 6.5 kb for the larger message and from
ÿ1461 nucleotides) had no further effect on reporter
3 kb to 4.6 kb for the smaller mRNA. The difference
gene expression. However, SCF core promoter acti-
in the size of the mRNA transcripts is due to the
vity could be greatly enhanced by treating cells with
length of the 30 UTR which is determined by the use
cAMP or forskolin (previously shown to increase
of one of two polyadenylation sites (Anderson et al.,
SCF expression in Sertoli cells), suggesting that cAMP-
1990; Bedell et al., 1996). The largest SCF mRNA
dependent regulatory elements might play a role in
transcript predicted by sequence analysis is roughly
SCF gene activation. Human SCF promoter sequen-
5.4 kb and contains 197 nucleotides of 50 UTR, an
ces were also cloned into luciferase reporter constructs
ORF of 818 nucleotides and a 30 UTR of 4432
and analyzed for function by deletion analysis. The
nucleotides. The smaller mRNA differs in the length
shortest promoter construct that encompassed the
of the 30 UTR region which is 2732 nucleotides. There
core promoter activity activated by cAMP or forskolin
are 14 ATTA motifs in the 30 UTR of the SCF
contained sequences from ÿ167 to ‡109 nucleotides.
mRNA which have been shown to affect HGF mRNA
In comparison, promoter constructs that contained
stability and thereby could greatly affect protein levels
additional 50 sequences (from ÿ853 or ÿ2185 nucleo-
(Shaw and Kamen, 1986; Bedell et al., 1996).
tides) showed the same increase in reporter activity in
cells treated with cAMP; however, basal levels of
reporter activity were significantly reduced, suggest-
Regulatory sites and corresponding ing the potential for negative regulatory elements.
transcription factors
A comparison of the 50 flanking sequences of mouse,
rat, chicken, pig, and human SCF show a high degree Cells and tissues that express
of homology (82±94% identity) within a 110 nucleo- the gene
tide interval upstream of the initiator methionine that
includes a GGCGGG motif representing the core See section on Cellular sources that produce SCF.
880 Jonathan Roy Keller and Diana Marie Linnekin

Figure 2 Human SCF promoter DNA sequence. The DNA sequence of the upstream region of the SCF gene is shown,
including the first five codons and corresponding amino acids of Exon 1 is underlined. DNA sequence elements that are
homologous to transcription factor-binding elements are also underlined and indicated above the sequence. TATA and
CAT box sequences are underlined and indicated above the sequence. The transcription start site is shown as a red arrow.

PROTEIN and the transmembrane region are shown in the

Accession numbers
SCF cDNAs isolated from a variety of species encode
proteins of roughly 273 amino acids including mouse
(SwissProt: P20826) (Anderson et al., 1990; Huang
et al., 1990; Zsebo et al., 1990a), human (SwissProt:
P21583) (Martin et al., 1990), and rat (SwissProt:
P21581) (Martin et al., 1990), pig (SwissProt: Q29030)
(Zhang and Anthony, 1994), chicken (SwissProt:
Q09108) (Zhou et al., 1993), dog (SwissProt: Q06220)
(Shull et al., 1992).
Sequence
The amino acid sequences for SCF from human,
mouse, pig, cat, and dog have been aligned and show
a strong degree of conservation across species
(Figure 3). The 25 amino acid signal peptide sequence
boxed areas. SCF protein sequences that are con-
served between species are shown in red shaded
letters. Black shaded letters indicate conservative
amino acid differences between species while all other
amino acid differences are shown as nonshaded black
letters. Mouse and human proteins show an overall
amino acid identity of 82% with 92% identity in the
cytoplasmic domain.
Description of protein
SCF protein is produced in both soluble and mem-
brane-bound forms (Anderson et al., 1990, 1991).
These isoforms arise from two differentially spliced
cDNAs. One cDNA encodes a 273 amino acid pre-
cursor that contains a cleavable 25 amino acid N-
terminal signal peptide and gives rise to the 248 amino
acid transmembrane protein SCF248 also known as
KL-1 or SCF-1. SCF248 is comprised of a 189 amino
 Stem Cell Factor 881

Figure 3 Alignment of SCF amino acid sequences. Human, murine, porcine, feline and
canine SCF amino acid sequences were aligned. The signal peptide and transmembrane
regions of SCF are shown in the boxed areas. Identical SCF amino acids between species are
shown in red shaded letters. Black shaded letters indicate conservative amino acid changes
between species, while black nonshaded letters indicate amino acid divergence between
species. The four cysteines involved in the intrachain disulfide bonds are shown in shaded
yellow letters. (Full colour figure can be viewed online.)
882 Jonathan Roy Keller and Diana Marie Linnekin
acid extracellular peptide domain, a 22 amino acid
membrane-spanning region (from amino acids 190 to
212 of SCF248) and a short 36 amino acid intracellular
cytoplasmic tail (amino acids 212±248) (see Figure 1).
SCF248 can be proteolytically cleaved to give rise to
soluble SCF, which contains the first 164 amino acids
of SCF248. The alternatively spliced form of SCF
cDNA encodes a shorter 220 amino acid transmem-
brane protein SCF220, also known as KL-2 or SCF-2,
that is identical to SCF248 except that it lacks amino
acids 147±177 (encoded by exon 6), which contains a
proteolytic cleavage site important for the production
of soluble SCF. This transcript arises from the use
of an alternative 30 splice acceptor site in the RNA,
which skips the 84 nucleotides contained within
exon 6. A second proteolytic cleavage site in mouse
SCF has been identified between amino acids 178±181
(12 amino acids in exon 7) that can be used in vitro to
generate soluble SCF; however, whether or not this
site is used in vivo is unknown (Huang et al., 1992;
Toksoz et al., 1992; Majumdar et al., 1994).
The soluble form of the SCF protein (164 amino
acids) forms noncovalently linked homodimers that
have extensive N- and O-linked glycosylation with an
apparent molecular mass of 50±60 kDa. SCF dimers
are required for SCF receptor dimerization, receptor
transphosphorylation, activation, and signal trans-
duction (Lev et al., 1992; Heldin, 1995; Hsu et al., 1997).
In this regard, dimerization defective isoforms of SCF
show greatly reduced biological activity including the
ability to bind SCFR. The majority of soluble SCF
exists as a monomer in serum because it is in low
concentration; however, it is predicted that trans-
membrane SCF exists predominantly as dimers
because of the enhanced probability for SCF mono-
mers to interact with each other and form dimers in
the membrane.
The exact physiological role(s) of soluble and
membrane-bound SCF are not fully understood.
However, analysis of mouse strains with naturally
occurring mutations in the SCF gene have provided
some insights into the importance of these two
isoforms (also described in the knockout and trans-
gene sections below). In particular, a mutation of
SCF in one mouse strain, steel-dickie (Sl d ), results in
the production of soluble but not transmembrane
SCF (Flannagan and Leder, 1990; Brannan et al.,
1991). Homozygous Sl d mice are viable but they have
complete lack of skin pigmentation, are sterile, show
severe anemia, and are mast cell deficient. Thus, it is
speculated that the membrane-associated form of
SCF is critical for normal mouse development, sug-
gesting that some of the important biological effects
of SCF are mediated through juxtacrine stimulation
of target cell populations (stimulation through
membrane-bound ligands). While it is not known
whether the levels of soluble SCF are significantly
reduced in Sl d homozygous mice compared with wild-
type mice and might also contribute to the phenotype,
administration of purified SCF to Sl d homozygous
mice increases the hematocrit, and mast cell numbers
at the site of injection, suggesting that a portion of the
hematological effects in Sl d homozygous mice can
be reversed by administration of soluble SCF (Zsebo
et al., 1990b). Furthermore, studies comparing the
expression of soluble and membrane-bound isoforms
of SCF in vitro have shown that human hematopoie-
tic cell growth can be maintained for longer periods
on stromal cells that express transmembrane SCF
(SCF220) in comparison with stromal cells that
express SCF248 which is cleaved to produce soluble
SCF (Toksoz et al., 1992). In addition, the survival
and proliferation of factor-dependent hematopoietic
cell lines are enhanced when they are co-cultured on
stromal cells that express a noncleavable variant of
transmembrane SCF (SCFx9/D3) versus SCF248 (Kapur
et al., 1998). Thus, transmembrane SCF may be
critical for the maintenance and survival of primitive
hematopoietic progenitor cells and for mast cell
accumulation and proliferation. Finally, the mem-
brane-bound isoform of SCF can also function as an
adhesion molecule for mast cells and hematopoietic
progenitor cells (Kaneko et al., 1991; Adachi et al.,
1992; Avraham et al., 1992; Long et al., 1992; Kodama
et al., 1994).
Discussion of crystal structure
The structure of SCF has not been directly deter-
mined; however, a model has been predicted based on
the published structural model for M-CSF that was
determined at 2.5 AÊ by X-ray crystallography (Bazan,
1991; Pandit et al., 1992) (Figure 4). There are four
antiparallel (helical bundles (I, II, III, and IV) which
are connected by two overhand loops. Thus far, all
other examples of four  helix proteins have been
identified as cytokines including GM-CSF, growth
hormone, and IL-4 (Bazan, 1991). The four cysteine
residues in SCF are proposed to be involved in intra-
molecular disulfide bonds, which contribute to the
three-dimensional structure of the protein (Figure 4).
The intramolecular disulfide pairs are Cys4±Cys89
and Cys43±Cys138, both of which are critical for full
biological activity (Nishikawa et al., 1992; Langley
et al., 1994; Jones et al., 1996). The same four Cys
residues are conserved between other family mem-
bers, including M-CSF and Flt-3 ligand (Flt-3L).
However, M-CSF contains three additional Cys resi-
dues, two that are involved in another intramolecular

Figure 4 A molecular model of human SCF. This
model is based on the published structure of human
M-CSF (reprinted with permission from Broudy, 1997,
copyright 1997, Blood). The SCF four helical bundles
are shown (I, II, III, IV) and the location of the
intramolecular bonds is indicated with yellow balls.
(Full colour figure can be viewed online.)
disulfide bond and one that is involved in an
intermolecular disulfide bond (between M-CSF
monomers) (Bazan, 1991; Pandit et al., 1992). Thus far,
no intermolecular bonds between SCF monomers
have been identified, however, it is speculated that
there is a large area of contact between SCF mono-
mers which is sufficient for stable dimer formation.
Truncation mutational analysis of SCF protein
indicates that the majority of the extracellular se-
quences (those present in the soluble form of SCF) are
required for biological activity (first 141 of 164
residues) (Nishikawa et al., 1992; Langley et al., 1994).
Studies of mouse and human SCF chimeras
demonstrate that SCF residues 1±35 and 79±97
located in the first and third  helix are required for
SCF's ability to synergize with GM-CSF (Matous
et al., 1996). In agreement with this study, the se-
quences recognized by one neutralizing SCF mono-
clonal mapped to residues Leu79 and Asn97. Another
region between 121 and 128 in the fourth helix is also
required for synergistic responses with GM-CSF.
Important homologies
SCF, Flt-3 ligand, and M-CSF are all type I trans-
membrane proteins with short cytoplasmic domains
Stem Cell Factor 883
that share significant structural homologies as
discussed in the crystal structure section above. These
include conserved cysteine residues, the four helix
bundle structure and the transmembrane domain.
Posttranslational modifications
Mouse and human SCF are extensively glycosylated
and contain both N- and O-linked sugars (Anderson
et al., 1990; Huang et al., 1990; Arakawa et al., 1991).
In particular, the predicted molecular mass of
monomeric SCF is 18,589 kDa, which is close to the
molecular weight of E. coli-derived SCF which
migrates at an apparent molecular weight of 18.5 kDa
on SDS-PAGE (Arakawa et al., 1991). In compari-
son, natural and CHO-derived monomeric forms of
SCF migrate on SDS-PAGE with an apparent
molecular mass of 28±35 kDa, which can be reduced
to 18.5 kDa by removal of both O- and N-linked
sugars, indicating extensive glycosylation (30% by
weight) (Zsebo et al., 1990a; Arakawa et al., 1991; Lu
et al., 1992; Langley et al., 1992).
CELLULAR SOURCES AND
TISSUE EXPRESSION
Cellular sources that produce
Analysis of SCF gene expression in the developing
embryo suggests that this gene has multiple functional
roles in development. For example, the SCF gene is
expressed along the migratory pathways for stem cells
that give rise to hematopoietic, melanocyte, and germ
cell lineages as indicated by in situ hybridization
and northern blot analysis (Matsui et al., 1990; Motro
et al., 1991; Keshet et al., 1991). Specifically, SCF is
expressed in the genital ridge of day 10 embryos,
while the receptor (SCFR) is expressed in the migrat-
ing germ cells. SCF expression in the genital ridge
decreases after day 11.5 of gestation but remains high
in the developing gonads during sexual differential
(both in the testes and ovary). This pattern of expres-
sion suggests that SCF is involved in regulating the
migration, proliferation, and differentiation of germ
cells, which is in agreement with the sterile phenotype
of Sl mice. Similarly, SCF is expressed in mesenchy-
mal cells located in the limb bud where melanocyte
precursors colonize while SCFR is expressed on the
migrating cells. The expression of SCF persists during
and after stem cell colonization of the limb buds. SCF
884 Jonathan Roy Keller and Diana Marie Linnekin

is also expressed in fetal liver, which is the migratory follicle-stimulating hormone (FSH), growth hor-
site for hematopoietic stem cells in the developing mone-releasing hormone (GHRH), forskolin, and
embryo between embryonic days 12 and 17. As would cholera toxin.
be predicted, there is a marked reduction in the
number of SCFR-positive stem cells that migrate to
the fetal livers of Sl/Sl embryos. SCF mRNA trans-
cripts were also detected in other tissues in the
developing embryo, including the spinal cord, fore-
brain, cerebellum, and olfactory bulbs, suggesting
that SCF might play a role in the developing CNS.
While there are no gross neurological defects in Sl
mutant mice, Sl/Sl d mutant mice show a defect in
hippocampal-dependent learning (spatial learning)
(Motro et al., 1996).
SCF is expressed by stromal or accessory cells in
the adult where these cells constitute the hematopoie-
tic microenvironment and include endothelial cells,
monocytes, and fibroblasts (Flannagan and Leder,
1990; McNiece et al., 1991a; Aye et al., 1992; Heinrich
et al., 1993; Linenberger et al., 1995; Broudy et al.,
1996). SCF is also produced by intestinal epithelial
cells, Sertoli cells, and follicular cells that surround
oocytes in the gonads, in thymic stroma and brain
cells, including those that constitute the olfactory
bulb, thalamus, cerebellum, and brainstem (Tajima
et al., 1991; deCastro et al., 1994; Klimpel et al., 1995).
SCF expression has also been detected in human
CD34-positive cells and keratinocytes in the skin
(Longley et al., 1993; Ratajczak et al., 1995). While
mRNA levels for the alternatively spliced variants of
SCF, SCF220, and SCF248 vary considerably between
tissues, SCF248 expression is the predominant species
in fibroblasts, brain, thymus, spleen, and bone
marrow, while SCF220 is prominent in placenta, cere-
bellum, and testes (Huang et al., 1992; Brannan et al.,
1991). The mechanisms responsible for regulating the
levels of alternatively spliced SCF mRNA are unknown,
as are the enzyme(s) responsible for the proteolytic
cleavage of SCF248 that produce soluble SCF.
Eliciting and inhibitory stimuli,
including exogenous and
endogenous modulators
Inflammatory stimuli including IL-1, TNF, and
bacterial pathogens can induce SCF production
in vitro by bone marrow stromal cells including
endothelial cells and fibroblasts (Anderson et al.,
1990; Koenig et al., 1994; Linenberger et al., 1995).
In other tissues, SCF can be induced in Sertoli cells
with dibutyryl cAMP, and agents that increase the
production of intracellular cAMP levels, including
Both TGF and TNF have been shown to
directly inhibit SCF-mediated growth and survival
effects on hematopoietic cell progenitors in vitro and
in vivo (Keller et al., 1992; McNiece et al., 1992;
Jacobsen et al., 1994, 1995a, 1995b, 1996). Local
administration of glucocorticoids at sites of allergic
inflammation in vivo significantly decreases mast cell
numbers and inhibits SCF production (Finotto et al.,
1997). The effect of glucocorticoids on mast cell
numbers was reversed by exogenous SCF, suggesting
that SCF is required for the growth and survival of
mast cells at local sites of allergy in vivo.
SCF mRNA levels are increased in bone marrow
and spleen cells from mice that were previously
treated with 5-fluorouracil (5-FU), a myeloablative
chemotherapeutic agent (Hunt et al., 1992; van Os
et al., 1997). SCF expression was also increased in
bone marrow cells from mice that had received a
sublethal dose of gamma-irradiation, suggesting that
increased SCF mRNA and protein levels may be a
crucial part of the host response to hematopoietic
injury (Limmani et al., 1995). In this regard, admini-
stration of antibodies that inhibit SCF's ability to
bind to its receptor greatly increases the sensitivity of
mice to irradiation, suggesting that SCF may play a
crucial role in recovery of hematopoietic cells from
radiation-induced hypoplasia. In this regard, admin-
istration of SCF alone has been shown to protect
mice from the lethal effects of irradiation (Zsebo et al.,
1992). Furthermore, it is known that IL-1 or TNF
can protect mice from the lethal effects of irradiation,
and that IL-1-mediated radioprotection can be pre-
vented by administration of antibodies which block
SCF/SCFR binding, indicating that IL-1's effects are
mediated, in part, through SCF (Neta et al., 1993).
While the levels of SCF mRNA expression have not
been determined in cells from patients that have
received myeloablative chemotherapy or radiation
therapy, the concentration of soluble SCF in normal
human serum ranges from roughly 1 to 3 ng/mL and
is not increased in the serum from patients with
myelodysplasia or aplastic anemia (Langley et al., 1993;
Bowen et al., 1993; Testa et al., 1994; Abkowitz et al.,
1996). Furthermore, the levels of SCF expression do
not significantly differ between stromal cells from
aplastic anemic patients and stromal cells from
normal donors, suggesting that levels of soluble
SCF are not predictive for those hematopoietic dis-
orders examined. In summary, as is the case for many
HGFs, the physiological mechanisms and signals
responsible for regulating SCF levels in vivo are
unknown.

RECEPTOR UTILIZATION
SCF utilizes the SCF receptor, which is member of
the type III receptor tyrosine kinase family that
includes c-Fms and PDGFR and Flk-2/Flt-3 recep-
tors (Besmer et al., 1986; Yarden et al., 1987; Qiu
et al., 1988; Ullrich and Schlessinger, 1990). The SCFR
receptor has been given the designation CD117.
IN VITRO ACTIVITIES
In vitro findings
SCF alone has little or no direct effect on the
proliferation of primitive and more committed
human and mouse hematopoietic progenitor cells,
or stem cells in other tissues. However; in the presence
of other HGFs, SCF stimulates the proliferation of
hematopoietic cells in soft agar (size and number of
colonies) and liquid cultures (Broxmeyer et al.,
1991a,b; de Vries et al., 1991; Lowry et al., 1991;
Metcalf and Nicola, 1991; Migliaccio et al., 1991a,b;
Tsuji et al., 1991; Williams et al., 1992; Ku et al.,
1996; Ramsfjell et al., 1996, 1997). For example, SCF
directly synergizes with (a) erythropoietin (EPO) to
promote unilineage erythroid colony formation
(burst-forming units ± erythroid, BFU-E), (b) IL-3
to promote multilineage colony formation (colony-
forming unit ± multipotential, CFU-multi) containing
granulocytes, macrophages, mast cells, and megakar-
yocytes (and erythroid cells in the presence of EPO),
(c) GM-CSF to promote granulocyte±macrophage
(GM) colony formation, (d) M-CSF or G-CSF to
promote unilineage CFU-G and CFU-M colony
formation respectively, and (e) thrombopoietin (TPO)
to stimulate megakaryocytic colony formation in
soft agar.
SCF in combination with multiple HGF combina-
tions that include IL-3, IL-6, and G-CSF can support
the expansion of progenitor cells in liquid culture
including BFU-E, CFU-multi, CFU-G, CFU-M, and
CFU-GM (Bernstein et al., 1991a; Migliaccio et al.,
1992; Haylock et al., 1992; Brandt et al., 1992). While
the combination of HGFs (SCF, IL-3, G-CSF, IL-6
(or IL-11)) can promote the expansion of committed
progenitor cells in vitro, it does not significantly
expand the number of pluripotential hematopoietic
stem cells (PHSCs), which are capable of reconstitut-
ing the entire hematopoietic system, including
lymphoid cells, myeloid cells, erythroid cells, and
megakaryocytes when transplanted in vivo (Peters
et al., 1996). In fact, inclusion of IL-3 in these HGF
Stem Cell Factor 885
combinations consistently reduces the lymphoid
repopulating ability of the surviving PHSC popula-
tion, while combinations of SCF and IL-11 maintain
PHSC activity in liquid culture (Hirayama et al.,
1992, 1994; Holyoake et al., 1996). SCF by itself is a
potent survival factor for primitive PHSCs and can be
used to transiently maintain the survival of PHSCs
and their more committed progeny in vitro (Leary
et al., 1992; Li and Johnson, 1994; Keller et al., 1995).
Thus far, SCF does not affect the self-renewal
capability of stem cells alone or in combination with
other HGFs in vitro.
Mouse PHSCs and human PHSCs can be main-
tained in co-cultures with stromal, adherent, or
accessory cell populations for extended periods in vitro
(Dexter et al., 1977). The presence of PHSCs in these
cultures is monitored by the continued production of
progenitor cells [CFU ± spleen (CFU-s) or cells that
form macroscopic spleen colonies when transplanted
into irradiated mouse recipients, CFU ± culture
(CFU-c), and their differentiated progeny (total cell
output)] over time in the nonadherent fraction of
these cultures. Antibodies that block SCF/SCFR
interactions inhibit the production of CFU-s, CFU-c,
and total cell number to nearly undetectable
levels indicating that SCF is absolutely required to
maintain hematopoietic development in these cultures
(Kodama et al., 1992; Wineman et al., 1993; Miller
et al., 1997).
Interestingly, the survival and maintenance of the
PHSC population was not impaired in the continued
presence of the SCF-blocking antibodies since hema-
topoiesis could be restored in these cultures when the
antibodies were removed. The presence of PHSCs was
also confirmed in these cultures by transplanting cells
into lethally irradiated mouse recipients in competi-
tive repopulating assays, which are designed to detect
PHSC activity. PHSCs can also be maintained on
stromal cells that do not produce SCF. Taken together,
SCF can promote the survival of PHSCs and is
absolutely required to maintain hematopoietic
development in vitro and in vivo, however, there are
other HGF or microenvironmental signals that can
support the survival and development of the SCFR-
expressing PHSCs (Kodoma et al., 1992; Wineman
et al., 1993; Ortiz et al., 1999).
SCF can synergize with IL-7 to stimulate pro-B cell
proliferation, however, SCF is not required for pre-B
cells to further differentiate and it does not induce the
proliferation of B220‡ cytoplasmic ‡ pre-B cells
(Rolink et al., 1991; McNiece et al., 1991b; Billips
et al., 1992; Funk et al., 1993). Further, while SCF
can affect primitive B cell progenitor cell growth
in vitro, there is not a strict requirement for SCF in B
cell development because, (1) pro-B cell numbers can
886 Jonathan Roy Keller and Diana Marie Linnekin
expand on stromal cells that do not produce SCF,
and (2) W/W fetal liver cells that lack SCFR expres-
sion can differentiate into B cells in RAG2 knockout
mice, which lack mature B cells (Rolink et al., 1991;
Faust et al., 1993; Takeda et al., 1997). In compari-
son, there is a critical role for SCF in early T cell
development. SCF can synergize with IL-7 to
stimulate the proliferation of primitive CD4ÿ CD8ÿ
CD3ÿ thymocytes but not more differentiated single
CD4‡ or CD8‡ cells (Godfrey et al., 1992; deCastro
et al., 1994; Morrissey et al., 1994). Furthermore, T
cell development is also defective in W/W and Sl/Sl
mice where the genes for SCFR and SCF have been
completely deleted respectively. In addition, W/W
fetal liver cells do not give rise to thymocytes when
transplanted into RAG2 knockout mice (Rodewald
et al., 1995; Takeda et al., 1997).
The receptor for SCF, SCFR, is expressed on the
majority of hematopoietic progenitors but is not
expressed on their differentiated progeny including
mature myeloid and monocytic cells or lymphoid and
erythroid cell populations; however, its expression is
maintained at high levels on mast cells. In this regard,
SCF promotes the survival, proliferation and differ-
entiation of mast cellsin vitro (Tsai et al., 1991a,
1991b; Iemura et al., 1994). In addition, SCF in
combination with IL-3 and IL-4 promotes the
proliferation of mast cells and their progenitors
(Kirshenbaum et al., 1992; Rennick et al., 1995). SCF
can promote the growth and differentiation of natural
killer (NK) cells in combination with IL-2, IL-7, or
IL-15in vitro (Matos et al., 1993; Silva et al., 1994;
Shibuya et al., 1995; Mrozek et al., 1996). SCF can
also promote the proliferation of the highly effective
antigen-presenting dendritic cell population in re-
sponse to GM-CSF or GM-CSF plus TNF (Young
et al., 1995; Szabolcs et al., 1995).
SCF can promote the adhesion of mast cells,
hematopoietic progenitor cells and cell lines to
fibronectin or vascular cell adhesion molecule 1
(VCAM-1) expressed on endothelial cells by activat-
ing VLA-4 and VLA-5 integrin expression on pro-
genitor cells (Kinashi and Springer, 1994; Dastych
and Metcalfe, 1994; Kovach et al., 1995; Levesque,
1996). Membrane-bound SCF can also function as
an adhesion molecule for mast cells and progenitor
cells which express SCFR (Kaneko et al., 1991; Long
et al., 1992; Kodama et al., 1994; Broudy et al., 1996).
As discussed above, SCF is expressed along the
migratory routes for germ cells, melanocytes and
hematopoietic cells, allowing these cells to home to
proper developmental sites. In this regard, SCF is also
a potent chemoattractant for mast cells and progeni-
tor cells (Meininger et al., 1992; Nilsson et al., 1994;
Okumura et al., 1996).
Regulatory molecules: Inhibitors
and enhancers
See section on Eliciting and inhibitory stimuli, includ-
ing exogenous and endogenous modulators.
Bioassays used
The majority of murine factor-dependent cell lines
derived from mouse hematopoietic tissues are IL-3-
dependent and require IL-3 for their continued
proliferation in vitro. However, some of these cell
lines also proliferate in response to murine SCF,
including the mast cell lines MC/9 and H-7 originally
used to purify SCF, and some subclones of FDC-P1
that were also used to purify IL-3 (Dexter et al., 1980;
Martin et al., 1990). In addition, there are SCF-
dependent cell lines, including EML (Tsai et al.,
1994), that require SCF for their continued growth
and proliferation. Human factor-dependent cell lines
have been established by culturing patient leukemic
cells in the presence of HGF in vitro and include
the cell lines MO7e and MB-O2 (Avanzi et al., 1990;
Hendrie et al., 1991; Broudy et al., 1993). These cell
lines proliferate in response to SCF in a dose-
dependent manner and represent sensitive and reliable
bioassays to determine the specific activity of mouse
and human SCF. It should be noted that rodent SCF
is active on human cells, while human SCF is 100-fold
less active on rodent cell lines, therefore, bioassays
require mouse or human cell lines where appropriate
(Martin et al., 1990).
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Normal physiological roles
A single injection of SCF to normal mice promotes a
dose-dependent increase in total number of peripheral
blood leukocytes, including neutrophils and imma-
ture myeloid cells but not circulating platelets or red
cells (Ulich et al., 1991). While total bone marrow
cellularity was not significantly altered by this treat-
ment, bone marrow morphology appeared more
primitive with a decrease in the number of mature
neutrophils and an increase in the number of
primitive myeloid and erythroid cells (Molineux
et al., 1991; Ulich et al., 1991). Daily injections of

SCF for 2 weeks in rodents and nonhuman primates
promoted a mast cell hyperplasia in many tissues
including the bone marrow (Tsai, 1991b; Galli et al.,
1993). Daily injections of SCF in nonhuman primates
resulted in increased numbers of neutrophils and
lymphocytes; however, in contrast to the rodents,
increased numbers of basophils, eosinophils, and
monocytes were also observed (Andrews et al., 1991).
Administration of SCF to rodents also increases the
number of progenitors, including CFU-s, short-term
reconstituting cells (STRCs ± radioprotective when
transplanted in vivo), and PHSCs in the bone marrow,
peripheral blood, and spleen (increased spleen size
and cell number) (Molineux et al., 1991; Fleming
et al., 1993; Bodine et al., 1993; Briddell et al., 1993;
de Revel et al., 1994; Yan et al., 1995). This is a con-
sequence of SCF-induced progenitor/stem cell mobi-
lization and redistribution as well as effects on
proliferation and expansion of progenitor cells includ-
ing PHSCs (Bodine et al., 1993; Fleming et al., 1993;
Harrison et al., 1994).
Increased numbers of hematopoietic progenitor
cells, including those capable of engrafting lethally
irradiated baboons, were observed in the peripheral
blood and bone marrow of nonhuman primates
treated with SCF and could be increased up to 100±
1000-fold in the circulation (Andrews et al., 1991,
1992). SCF in combination with G-CSF was more
effective in mobilizing progenitor/stem cells capable
of protecting lethally irradiated baboons; however,
whether these progenitors include PHSCs remains to
be determined (Andrews et al., 1994, 1995; McNiece
and Briddell, 1995). In comparison, the combination
of SCF and G-CSF showed a rapid increase in the
number of PHSCs in the peripheral blood and bone
marrow of mice after 14 days (Bodine et al., 1996).
Thus, SCF alone or in combination with G-CSF
effectively mobilizes stem cells into the periphery
and provides a convenient source of stem cells for
transplantation.
SCF has also been shown to be critical for main-
taining constitutive hematopoiesis in studies where
animals were administered antibodies that block SCF
function by inhibiting the binding of SCF to its
receptor. Treatment of mice with 1 mg of antibody
every other day for 2 weeks resulted in the elimination
of erythroid cells followed by myeloid cells, while
total bone marrow cellularity remained unchanged.
However, the majority of cells (90%) found in the
bone marrow were B220-positive (normally 30±40%),
including pre-B cells that express cytoplasmic 
chains, and IgM-bearing B lymphocytes (Ogawa et al.,
1991; Rico-Vargas et al., 1994). Myeloid progenitor
cell populations including those that respond to IL-3,
GM-CSF, and M-CSF declined after a single
Stem Cell Factor 887
antibody injection while the number of progenitors
that respond to IL-7 increased. The majority of the
committed CFU-s day 8 and more primitive CFU-s
day 12 colonies were also eliminated from the bone
marrow by this treatment in vivo, however, CFU-s
day 12 progenitors were not completely eliminated. In
similar experiments looking at other organ systems,
adult spermatogenesis and melanocyte development
were also blocked by the administration of these
antibodies in vivo (Nishikawa et al., 1991). These
antibodies also inhibited SCFR/SCF expression in
fetal tissues and specifically blocked fetal thymic
colonization by triple negative fetal liver progenitors
in vitro (Godfrey et al., 1994). Furthermore, these
antibodies also inhibit the development of CD4‡
CD8‡ cells in fetal thymus reconstitution assays
(Hozumi et al., 1994). Taken together, these data
suggest that SCF is critical for the development of
most hematopoietic cell lineages except B cells.
Species differences
Although mouse and human SCF are roughly 82%
identical at the amino acid level, human SCF is
100-fold less active on mouse cells, while mouse
and rat SCF are equally active on both human and
rodent cells.
Knockout mouse phenotypes
The phenotypes of mice with naturally occurring
mutations in SCF or the Sl locus demonstrate that the
SCF/SCFR axis is critical for hematopoiesis, mela-
nogenesis, and gametogenesis. Sl mutant mice that
have completely deleted the coding sequences for
SCF do not produce viable homozygous offspring;
embryos only survive to roughly 15 days gestation. In
comparison, Sl mutant mice where SCF sequences are
present, produce viable homozygous offspring that
show defects in hematopoietic development, pigment-
ation, and germ cell development (sterility) depending
on the severity of the mutation. Thus, null alleles are
lethal, while viable alleles retain some of the normal
function of SCF (summarized in Table 1). For
example, Sl gb, Sl J, Sl10H, Sl, Sl 8H, Sl 12H, and Sl 18H
have complete deletions of the SCF gene and all
homozygous embryos die at roughly 15 days gesta-
tion with severe defects in fetal liver hematopoiesis
without effects on other organ systems (Russell, 1979;
Silvers, 1979; Copeland et al., 1990; Huang et al.,
1990; Zsebo et al., 1990b). The smallest complete
deletion in SCF coding sequences occurs in Sl gb mice
where the total genomic deletion is roughly 120 kb.
888 Jonathan Roy Keller and Diana Marie Linnekin

Table 1 Summary of Steel locus mutants

Gene symbol Gene name Mutation Consequence of mutation Phenotype of

homozygous mice

Sl gb Steel-Grizzle Belly 120 kb deletion Absence of SCF Prenatal lethality

J
Sl Steel-J 650 kb deletion Absence of SCF Prenatal lethality
10H
Sl Steel-10H 680 kb deletion Absence of SCF Prenatal lethality
Sl Steel > 810 kb deletion Absence of SCF Prenatal lethality
Sl d Steel dickie 4 kb intragenic deletion Lack of membrane-bound Severely anemic
SCF
Lack of pigmentation
Sterility in both sexes
17H
Sl Steel-17H Point mutation Absence of normal Macrocytic anemia
in splice acceptor cytoplasmic SCF domain
White spotting
Male sterility
Sl pan Steel-Panda Rearrangement/ Decreased SCF expression Mild anemia
inversion >100 kb Decreased pigmentation
50 SCF gene
Female sterility
con
Sl Steel-contrasted Rearrangement Decreased SCF expression Mild anemia
0
> 100 kb 5 SCF gene Decreased pigmentation
Female sterility

This deletion begins in the 30 untranslated region of
SCF and includes the entire SCF coding sequences
of roughly 50 kb, as well as 60 kb of DNA sequence
50 of the SCF coding region (Bedell et al., 1996).
Furthermore, the deletions detected in Sl J and Sl10H
(larger than the deletion in Sl gb) are also smaller
deletions than those seen in the original Sl allele
where lethality occurred at the same time during
gestation. In summary, late gestation lethality appears
to be the true null phenotype; however, whether other
genes are deleted in Sl mice with larger genomic dele-
tions remains to be determined.
The best-characterized mouse strain with a natu-
rally occurring viable mutation of SCF is the Sl d/Sl d
mouse. These mice have a 4 kb intragenic deletion
which removes the exons encoding the transmem-
brane and cytoplasmic domains of SCF resulting in
the Sl d transcript, which encodes the soluble isoform
of SCF (Brannan et al., 1991; Flannagan et al., 1991).
These mice are viable but have severe macrocytic
anemia with mast cell deficiencies, sterility in both
sexes, and lack skin pigmentation. The bone marrow
of Sld is hypocellular with both myeloid and erythroid
progenitor cell deficiencies. Thus, it is speculated that
the membrane-associated form of SCF is critical for
the development of three distinct cell lineages,
including hematopoietic cells.
Another informative viable mutant of the Sl locus
is the Sl17H mutation, which is a splice site mutation
that causes exon 8 to be skipped, resulting in the
splicing of exon 7 with exon 9. The deletion of exon 8
which encodes the cytoplasmic domain of SCF results
in a frameshift mutation that replaces the normal
SCF cytoplasmic domain with extraneous amino
acids before a stop codon is encountered (Brannan
et al., 1992). This mutation does not affect the ability
of SCF to form dimers but slows the rate of SCF
transport to the cell surface and subsequent stability
(Tajima et al., 1998a). Total bone marrow cellularity,
leukocyte counts, platelets and hematocrit are un-
affected in these mice. However, myeloid progenitor
cells and tissue mast cells are slightly decreased. long-
term bone marrow culture cells (LTBMCs) estab-
lished from these mice show a greatly reduced ability
to support the production of total hematopoietic cell
output. Furthermore, these mice have reduced levels
of CFU-s progenitor cells. Further, male mice are
sterile while female mice are unaffected.
Two other Sl mouse strains including Sl pan and
Sl con have DNA rearrangements roughly 100 kb 50 of

the SCF coding sequences (Bedell et al., 1995). These
mutations affect SCF mRNA expression in the
gonads and lead to reduced numbers of primordial
germ cells and result in female sterility (male sterility
is not observed).
Transgenic overexpression
To better understand the physiological roles of
soluble versus membrane isoforms of SCF, Sl d
mice were engineered to stably express soluble and
membrane-restricted SCF transgenes. Both Sl d
transgenic mouse strains showed increases in the
number of multipotential and more committed
myeloid progenitor cells in the bone marrow and
increased numbers of peripheral blood leukocytes
(mainly neutrophils) (Kapur et al., 1998). However,
only Sl d mice that expressed the membrane-restricted
isoform of SCF showed (1) a reversal in the severe
runting phenotype, (2) an increase in bone marrow
cellularity, and (3) an increase in the hematocrit and
red cell count. However, neither transgene could
rescue the defects in germ cells, melanocytes, or mast
cells in Sl d mice. The lack of effect of either SCF
transgene on other organ systems may be due to the
choice of promoter in these constructs which could
have restricted the transgene expression to specific
cell types (Kapur et al., 1998). In other experiments,
transgenic mouse strains were engineered to exclu-
sively produce the membrane-restricted form of SCF
(SCF220 or KL-2) by homologous recombination
in embryonic stem cells. No effect on hematopoiesis
including peripheral blood counts or bone marrow
cellularity or progenitor numbers were observed in
these mice (Tajima et al., 1998b). Furthermore, there
were no observable effects on gametogenesis since
male and female mice produced normal numbers of
offspring. However, these mice showed defects in the
production of dermal mast cells, and were also
sensitive to sublethal doses of gamma-irradiation,
suggesting a role for soluble SCF in hematopoietic
recovery following radiation injury.
Because human SCF can act as an antagonist of
mouse SCF, transgenic mice were produced that
express human membrane-restricted SCF (SCF220)
to separate the effects of soluble and transmembrane
SCF (Kapur et al., 1997, 1998). No significant effect
on hematopoiesis was observed in these mice,
including total leukocyte counts and red cell numbers
in the peripheral blood, or bone marrow cellularity
and progenitor numbers. However, these mice have a
coat color defect, have greatly reduced numbers of
dermal mast cells, and show abnormal thymocyte
Stem Cell Factor 889
maturation, suggesting that melanoblasts, dermal
mast cells, and thymocyte progenitors are not able to
migrate to the appropriate sites, or are unable to
survive and proliferate once they arrive. Transgenic
mouse strains were constructed which restricted
the expression of SCF248 or SCF220 transgenes to
keratinocytes in normal mice (Kunisada et al., 1998).
These studies found that expression of SCF248 in
keratinocytes results in cutaneous mastocytosis and
epidermal hyperpigmentation due to the maintenance
of melanocytes and melanin production in the epi-
dermis. In comparison, expression of the membrane-
restricted form of SCF, SCF220, in keratinocytes
promoted epidermal melanocytosis and melanin
production without mastocytosis. This suggests that
soluble SCF is required for dermal mast cell migra-
tion and/or proliferation while membrane-associated
SCF is required for melanocyte growth and differ-
entiation. In other studies, expression of SCF248 in
keratinocytes also promoted pigmentation in sites
which normally do not contain melanocytes or their
precursors, suggesting that SCF can also stimulate the
migration of melanocytes in vivo (Kunisada et al.,
1998).
Pharmacological effects
None reported for mice.
Interactions with cytokine network
None reported in vivo.
Endogenous inhibitors and
enhancers
See section on Eliciting and inhibitory stimuli, includ-
ing exogenous and endogenous modulators.
PATHOPHYSIOLOGICAL ROLES
IN NORMAL HUMANS AND
DISEASE STATES AND
DIAGNOSTIC UTILITY
Normal levels and effects
Normal plasma levels of human SCF range from 1
to 5 ng/mL (Langley et al., 1993). In addition, SCF
levels do not significantly vary in patients with a
890 Jonathan Roy Keller and Diana Marie Linnekin
variety of hematological disorders including aplastic
anemia and myelodysplastic syndromes (McNiece
and Briddell, 1995; Kumar and Alter, 1998).
Role in experiments of nature and
disease states
While no abnormalities involving the SCF genetic loci
have been reported, locally high concentrations of
soluble SCF have been found in lesions of human
cutaneous mastocytosis (Longley et al., 1993, 1995).
This disease is characterized by accumulations of
mast cells as well as increases in the production of
epidermal melanin similar to that observed in trans-
genic animals that expressed SCF transgenes in
keratinocytes (described above). This has led to the
hypothesis that locally produced SCF can promote
mast cell hyperplasia.
IN THERAPY
Preclinical ± How does it affect
disease models in animals?
SCF administration to Sl/Sl d mice reverses the
macrocytic anemia resulting in increased mean red
blood cell volume and red blood cell counts that are
within 70±85% of their littermate control levels. This
effect was reversed when SCF treatment was stopped
(Hunt et al., 1992; Galli et al., 1994). Increased
numbers of lymphocytes and platelets were also
observed in Sl/Sl d mice treated with SCF, which were
also observed in normal mice treated with SCF.
Injection of SCF into Sl/Sl d mice caused a two-fold
and 20-fold increase in the number of primitive
progenitors (CFU-s day 12) found in the bone
marrow and spleen, respectively (Bodine et al., 1992).
Sl/Sl d mice do not experience a rebound in platelet
counts after 5-FU treatment, while normal mice show
an overshoot between 10 and 20 days post 5-FU
treatment (Hunt et al., 1992). To determine whether
SCF was critical for rebound (overshoot) thrombocy-
tosis after 5-FU treatment in Sl/Sl d mice, mice were
treated with SCF after 5-FU. Administration of SCF
to 5-FU-treated Sl/Sl d mice promoted the same over-
shoot as that seen in control 5-FU-treated mice,
demonstrating the importance of SCF in megakaryo-
cyte growth and development. Megakaryocyte pro-
genitor (CFU-MK) numbers are increased in the bone
marrow and spleen of normal mice treated with SCF,
while platelet counts are not increased in the peripheral
blood. Therefore, it is speculated that the major effect
of SCF treatment in Sl/Sl d mice is to promote the
proliferation of immature megakaryocytes and their
precursors, while other factors such as thrombopoietin
are critical for the final stages of platelet maturation.
Pharmacokinetics
Baseline SCF serum levels in patients that were to
receive SCF treatment in a phase I clinical trial were
roughly 1 ng/mL (Glaspy, 1996). SCF serum levels
reached a maximum 13±14 hours after the first dose
of SCF. Maximum serum SCF levels were observed
between 10 and 14 hours after subsequent doses and
SCF. Adsorption of SCF was relatively low after the
first dose of SCF.
Toxicity
The use of SCF in vivo has been limited due to adverse
side effects. These included dermatological reactions
such as pruritic wheals and edema at the site of
injection as well as increased melanization (pigmenta-
tion) of the epidermis at doses above 25 mg/kg body
weight over a 14-day period (Demetri et al., 1993;
Costa et al., 1996; Weaver et al., 1996; Moskowitz
et al., 1997). In addition, 10±20% of the patients
treated with SCF developed allergic-like reactions
characterized by urticaria with respiratory symptoms
that required discontinuation of treatment (Grichnik
et al., 1995; Costa et al., 1996). Because mast cell
hyperplasia was suspected in these cases, a prophy-
lactic antihistamine treatment was incorporated into
subsequent protocols (McNiece and Briddell, 1995).
Clinical results
A phase I clinical trial of SCF was conducted in lung
cancer and breast cancer patients who received 10±
50 mg/kg/day SCF by subcutaneous injection for 14
days (Glaspy, 1996; Demitri et al., 1993). An increase
in the total number of peripheral blood leukocytes
was observed prior to chemotherapy and some
acceleration in platelet and leukocyte numbers was
seen after chemotherapy. Daily administration of
SCF to patients at dosages of up to 50 mg/kg for 14
days did not affect the number of peripheral blood
CD34‡ cells; however, increased numbers of CD34‡
cells, that included both committed and more
primitive hematopoietic progenitor cells, were de-
tected in the bone marrow (Tong et al., 1993). SCF
therapy also promoted an increase in bone marrow

cellularity with significant increases in promyelocytes
without apparent effects on other marrow hemato-
poietic cells (Orazi et al., 1995).
Because SCF was shown to potently mobilize
progenitor cells in mice and nonhuman primates,
subsequent clinical trials have focused on the ability
of SCF (in lower doses) in combination with G-CSF
to mobilize peripheral blood progenitor cells for
transplantation. A phase I/II trial in non-Hodgkin's
lymphoma patients was performed to compare
mobilized peripheral blood progenitor cells for
autologous transplantation from patients treated
with the combination of SCF plus G-CSF or G-
CSF alone (Moskowitz et al., 1997). Patients trans-
planted with G-CSF plus SCF-mobilized peripheral
blood cells showed a decreased time to normal
platelet levels following chemotherapy compared with
transplanted G-CSF-mobilized peripheral blood. In
another phase II trial, fewer apheresis procedures
were required to collect sufficient numbers of peri-
pheral blood progenitor cells from breast cancer
patients for transplantation studies (Kumar and Alter,
1998). In a phase I study of patients with refractory
aplastic anemia, SCF was well tolerated at all doses
and patients that received SCF showed neutrophil
improvements that were improved by the combina-
tion with G-CSF (Kumar and Alter, 1998).
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ACKNOWLEDGEMENTS
The content of this publication does not necessarily
reflect the views or policies of the Department of
Health and Human Services, nor does mention of
trade names, commercial products, or organizations
imply endorsement by the U.S. Government.
We are grateful for the critical review of this
manuscript by Drs Sally Spence, Jon Dermott, and
J.J. Oppenheim. The publisher or recipient acknowl-
edges right of the U.S. Government to retain a
nonexclusive, royalty-free license in and to any copy-
right covering the article. This project has been
funded in whole or in part with Federal Funds from
the national Cancer Institute, National Institutes of
Health, under contract number NO1-CO-56000.