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Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 348-351
Do Stem Cells Play Dice?
By
T. Enver,
C.M. Heyworth, and
T.M. Dexter
From the Section of Gene Function and Regulation, Institute of Cancer
Research, Chester Beatty Laboratories, London, UK; and the CRC
Department of Haemopoietic Cell and Gene Therapeutics, Paterson
Institute for Cancer Research, Christie Hospital NHS Trust, Manchester,
UK.
THE DEBATE SURROUNDING the issue
of whether or not hematopoietic stem cell commitment and
differentiation are orchestrated in a cell-intrinsic or cell-extrinsic
fashion is in many ways akin to the nature versus nurture debate that
typifies discussions of human personal potentials. We have published
data that could be interpreted as supporting both
hypotheses.1-3 Simply put, the question is this: is
unilineage commitment the result of a cell-autonomous or internally
driven program or rather is it the consequence of a cell responding to
an external, ie, environmentally imposed, agenda?
In the former case, stochastic processes are often invoked as
instigators of lineage decisions. In instructive, or so-called deterministic schemes, cell-cell interactions or diffusible signals dictate cell fate decisions. Much attention has revolved around the
role played by hematopoietic growth factors in this process: do they
play an instructive, ie, a deterministic role, or are they
simply permissive or selective, ie, allow the survival and proliferation of independently committed cells? Certainly, experiments using multipotent cell lines in vitro suggest that the addition of
exogenous growth factors is essential for the survival and proliferation of the cells but not for the lineage commitment or
subsequent differentiation and development into mature
cells.1,3 However, it has been argued that cultured cell
lines, albeit with a normal karyotype, growth factor dependence, and
ability to undergo multilineage differentiation, may not adequately
reflect what happens with freshly isolated normal cells. To address
this criticism, the intuitive experiment of adding cytokines, alone or
in combination, to a population of multipotent cells in vitro and
recording lineage output would, on the face of it, be a simple way of
distinguishing between stochastic versus deterministic control of
differentiation. Unfortunately, this experiment is flawed. For example,
the elicitation of granulocytes from a pool of multipotent cells by the
addition of G-CSF would seem to argue for an instructive role for
G-CSF. However, the result could equally well be explained by
suggesting that G-CSF is selecting for the survival and proliferation
of a subpopulation of cells that have been already programmed for neutrophil development (by cell-intrinsic/stochastic means), with the
other cells, with different lineage potential, either remaining undeveloped/unexpanded or simply dying. In this respect, in vivo experiments with all the currently assessable knock-out mice lacking growth factors and/or their receptors have strongly suggested that growth factors are not essential for lineage determination. For
example, mice lacking GM-CSF show no obvious deficiencies in the
production of myeloid progenitor cells in the bone marrow4;
mice lacking G-CSF show a reduced but still substantial production of
neutrophils5; and the erythropoietin (Epo) and
Epo receptor knock-out mice still produce near-normal
levels of lineage-committed erythroid precursor cells.6
Although these data do not rule out the possibility that these growth
factors can be involved in lineage commitment decisions, the data do
show that lineage commitment decisions can be made in the absence of
these growth factors.
Further information has come from molecular studies of the cytokine
receptors themselves. While maintaining specific private ligand binding
domains, many receptors share common or public signaling domains.
Delivering a deterministic signal through common or shared subunits
poses something of a mechanistic conundrum and raises the familiar
specter of redundancy. Receptors that deliver signals through
homodimerization perhaps offer more potential for instructive
signaling, but even these appear to activate, if not identical, than
very similar or highly overlapping, downstream signaling pathways.
Noteworthy here, however, and potentially supportive of an instructive
role is the molecular delineation within the cytoplasmic signaling
domain of the G-CSF receptor of separable proliferation and
differentiation-associated regions.7,8
Attention has also focused on the expression pattern of the cytokine
receptors, particularly within multipotent cells: a cytokine-mediated instructive signal cannot be delivered to a multipotent cell that lacks
a receptor for it! Most recently, McKinstry et
al9 have examined receptor distribution on
purified stem and progenitor cells using radiolabeled cytokine ligands
as probes. Heterogeneity was observed both in terms of the percentage
of the population expressing receptors and the numbers of receptors
expressed by labeled cells. Expression levels were in many cases low
( 100 receptors/cell). Strikingly, the expression of receptors for
GM-CSF (GM-CSFR) and M-CSF (M-CSFR) on stem cells was below the level of detection, and M-CSFR could not be detected on progenitor cells despite the fact that these cell populations could functionally respond
to added GM-CSF or M-CSF.9,10 Similar results have been
documented by reverse transcription-polymerase chain reaction (RT-PCR)
analysis of single multipotent FDCP-mix A4 and sorted CD34+ lin mouse bone marrow
cells.11 Whereas heterogeneity was observed in these
studies (although more marked in A4 than in CD34+
lin cells), many individual cells coexpressed multiple
different receptors and, despite the low levels of expression seen,
could functionally respond to the appropriate ligands. These data may be argued both ways: heterogeneity favoring perhaps a stochastic view
and being consistent with the random assortment of blood cell lineages
reported many years ago by Ogawa12 and receptor coexpression on the other hand setting up the possibility of receiving an instructive cue from one or more of an assortment of cytokines.
Manipulation of cytokine and cytokine receptor expression both in vitro
and in vivo has been performed in many studies. Ectopic expression of
receptors in multipotent cells, largely through retroviral
transduction, has not led to a marked bias in lineage output but rather
elicited expansion of the multipotent compartment in response to the
cognate cytokine. For example, M-CSFR-transduced multipotent cells
proliferate in response to M-CSF but do not preferentially commit to an
M-CSF-affiliated pathway.13 One striking exception to this
pattern was reported by Borzillo et al,14 who ectopically
expressed the M-CSFR in an IL-7-dependent pre-B-cell line. The
addition of M-CSF resulted in a lymphoid to macrophage lineage switch.
Although this has been frequently interpreted as a deterministic event,
an alternative explanation is that there may be a default pathway for
differentiation that results in cells with macrophage-like
characteristics whose survival is enhanced by M-CSF. These results
should be contrasted with natural and engineered cytokine and cytokine
receptor loss of function mutants in mice.15 Despite the
multiplicity of these knock-outs, no evidence for any defects in
unilineage commitment has been observed. As with all knock-out studies,
the action of compensatory/parallel and/or redundant pathways,
obscuring an authentic in vivo role, cannot be ruled out, but the
results currently being obtained from the cross-breeding of different
knockouts makes this less likely.16 However, it should be
emphasized that, although unilineage commitment itself seems unimpaired
in these animals, the production of mature, functional, terminally
differentiated cells is, in many cases, severely affected, once again
arguing for a role for growth factors in the postcommitment
amplification and maturation phase. Similar data have been obtained
using hybrid receptors in which the signaling domains of given
receptors have been fused to the ligand binding domains of others or to
binding domains for synthetic ligands. A most recent and elegant
example of this has been provided by Stoffel et al17 at ASH
1997. These investigators have used a knock-in approach to express a
hybrid receptor consisting of the extracellular domain of c-mpl and the cytoplasmic domain of the G-CSFR under the control of the c-mpl regulatory elements. Once again, a nonspecific survival or
proliferation response was observed, but no changes in commitment bias
were detected, arguing against a deterministic role for growth factors in lineage commitment.
Because the signals themselves often activate similar if not identical
pathways, different outcomes could presumably be dependent on different
cellular perceptions or interpretations, ie, the notion of
context-dependent interpretation or cellular history. An example comes
from studies of the G-CSFR in which ectopic expression and activation
in hematopoietic cell lines can lead a proliferative response if
expressed in BAF3 cells, but induce differentiation if transfected into
L-GM cells.7
What then might likely constitute context at the molecular level? The
status of cross-regulatory or cross-talking signaling pathways
undoubtedly factor into the mix, but a more significant component is
likely provided by the transcription factor profiles of individual
multipotent cells. Many lineage-restricted or lineage-affiliated transcription factors have been described and their role in lineage specification addressed, primarily through gene targeting in
mice.18 Strikingly, there is not a yet a single example of
a resulting lineage-specific ablation at the level of commitment. That
is not to say that the hematopoietic systems of these animals are not
in many instances grossly affected with major defects in mature blood
cell development. For example, GATA-1 knockout mice are severely anemic
as a result of a failure in erythroid maturation, although erythroid
commitment (ie, progenitor numbers) is largely unimpaired. As with
growth factor receptors, the issue of overlapping functions and
expression patterns as well as compensating pathways may well as yet be
obscuring authentic roles for some of these transcription factors in
commitment. The next generation of multiple and conditional knockout
mice will undoubtedly help to resolve this.
Ectopic master gene experiments based on the myoD paradigm in muscle
have been conducted with some success, although primarily in chicken
cells. Kulessa et al19 have shown that ectopic expression of individual transcription factors can reprogram the lineage output of
myb-ets-transformed chicken progenitor cells. GATA-1 is a case in
point, and here quantitatively different levels of GATA-1 are
associated with different lineage outcomes suggesting that threshold
effects may be in play.19 Importantly, their work, as well
as our own, also emphasizes the role of negative regulation in lineage
specification.20-22 Rejection of other lineage options is
in some sense a corollary of unilineage commitment, and the observation
that transcription factors can promote one lineage program while
simultaneously and actively repressing another squares well with this.
The recent demonstration that Ikaros may function to sequester loci
into transcriptionally repressive regions of the nucleus may also be
important in this regard.23
Because lineage determination ultimately results from the collective
assembly of stable transcriptional complexes at lineage affiliated loci
such as  -globin, myeloperoxidase (mpo), Ig, etc, it is relatively
easy to see how transcription factors must play a crucial role in
differentiation through activation of a host of lineage-affiliated or
lineage-specific target genes. It is perhaps less obvious to imagine
how the ball starts rolling, and indeed rolling in any one particular
direction.
Some intriguing evidence has recently come to light from the detailed
molecular analysis of multipotent stem and progenitor cells. Studies of
chromatin structure of multipotent cells have shown that a number of
lineage-affiliated genes (globin, mpo, IgH, CD3 ) have
accessible control regions (enhancers/LCRs) before unilineage
commitment.24,25 This accessibility is reflected in the
fact that low-level, possibly spontaneous, transcription can be
detected from a number of these genes and that RT-PCR analysis of a
variety of differently purified multipotent cells has demonstrated expression of a variety of different lineage-affiliated transcription factors and cytokine receptors.11 Furthermore, analysis of
single cells has shown that many different lineage-affiliated
components can be expressed in the same cell, although heterogeneity in
specific patterns or profiles of expression was observed. These data
are consistent with a model of lineage specification of type shown in
Fig 1, in which low level multilineage gene
activity establishes a ground state or level of noise from which
regulatory networks can start to build and be amplified or diminished
either through quasi-random or stochastic changes in the components
(ie, spontaneous transcription of an accessible activator or repressor)
or through positive/negative reinforcement through extracellular
signalling via stochastically expressed receptor molecules. Such a
model incorporates both cell-extrinsic and cell-intrinsic components and may critically not be dependent on any one specific component to
instigate a commitment decision.
View larger version (64K):
[in this window]
[in a new window]
| Fig 1.
In this model, lineage-specific genes (a, b, and c) are
in a primed state in the multipotent progenitor cells, characterized by
open chromatin and some low-level of sporadic expression.
Lineage-affiliated regulators (colored shapes) are initially
coexpressed at levels that fluctuate within thresholds. This low-level
multilineage gene activity establishes a ground state from which
regulatory networks can develop through negative and positive feedback
loops.
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Finally, it should be noted that what is true for multipotent or stem
cells, which must service a lifetime's supply of blood cells, may not
hold for more developmentally restricted progenitor cells. If
differentiation of stem cells was simply instructive, it is difficult
to imagine how stem cell homeostasis can be maintained in the face of
competing demands for one of the stem cell lineages in response to
physiological insults. Notably, cell proliferation in the bone marrow
must be able to respond rapidly and efficiently to bleeding, infection,
etc, and here perhaps it is more reasonable to propose that growth
factors have a role to play in the differentiation of
lineage-restricted progenitor cells such as the bipotent
granulocyte-macrophage colony-forming cells (GM-CFC). Highly enriched
GM-CFC develop into granulocytes in the presence of SCF or G-CSF and
into macrophages if cultured in M-CSF. In a series of studies aimed at
investigating the molecular mechanisms underlying lineage restriction
in the presence of these growth factors, we showed that macrophage
development is associated with translocation of PKC
from the cytoplasm to the nucleus. Indeed, if GM-CFC are grown in the
presence of agents that translocate PKC to the nucleus (eg, TPA and
IL-4) even in presence of growth factors that usually promote
granulocytic development, macrophages develop.26,27
Similarly, using clonal analysis of paired daughter cells of GM-CFC,
Metcalf and Burgess28 showed that GM-CSF and M-CSF can
apparently irreversibly commit cells to different lineages. Thus,
certain of the growth factors may be able to play a role in lineage
determination of these bipotent GM-CFC via known regulatory mechanisms.
In conclusion, our current hypothesis is that primitive cell
differentiation involves mainly stochastic processes, but, as the cell
becomes more lineage restricted, deterministic processes appear to be
more relevant as the cell has to respond to immediate changes in the
environment. Ultimately, one cannot help feeling that the all or none
instructive versus selective debate is no longer the question. It is
clearly important now to piece together the different molecular
components, cell-intrinsic and cell-extrinsic, and understand the
circuitry of their interactions. The precise starting point of a
lineage-determining loop is probably not important. Indeed, it may vary
between cells and therefore be unknowable. It is the chicken and the
egg scenario all over again and who really cares which came
first apart from the chicken!
 |
FOOTNOTES |
Supported by the Cancer Research Campaign and the Leukaemia Research
Fund. T.M.D. is a Gibb Research Fellow.
Address reprint requests to T. Enver, PhD, Section of Gene
Function and Regulation, Institute of Cancer Research, Chester Beatty
Laboratories, London, SW3 6JB, UK; e-mail: tariq{at}icr.ac.uk.
| |
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