1 Histopathology Unit, Cancer Research (UK), London WC2A 3PX, UK
2 Department of Histopathology, Imperial College London at the Hammersmith
Hospital, London W12 ONN, UK
3 Department of Histopathology, Bart's and the London, Queen Mary's School of
Medicine and Dentistry, London E1 2AD, UK
* Author for correspondence (e-mail: m.alison{at}ic.ac.uk)
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Summary |
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Key words: Stem cells, Bone marrow, Transdifferentiation, Cell fusion
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Introduction |
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Within the past few months doubt has been cast upon claims that certain
adult stem cells, particularly from bone marrow and the central nervous
system, when removed from their familiar niches, can jump lineage boundaries
to generate completely new cell types. This has led to a stream of banner
headlines along the lines of `Cell fusion leads to confusion'
(Wurmser and Gage, 2002),
`Biologists question adult stem-cell versatility'
(DeWitt and Knight, 2002
),
`Plasticity: time for a reappraisal?'
(Holden and Vogel, 2002
), `Is
transdifferentiation in trouble? (Wells,
2002
) and `Are somatic stem cells pluripotent or
lineage-restricted? (D'Amour and Gage,
2002
). Here, we examine the key issues.
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The case for adult stem cells |
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Two recent publications in Nature, however, have suggested that
these phenomena could be due to the fusion of bone marrow cells with the
differentiated cells in the new organ for example, the liver. When
genetically altered bone marrow from GFP transgenic mice was mixed with ES
cells, a very small proportion of the bone marrow cells fused with the ES
cells (2-11 hybrid clones per 106 marrow cells), and these cells
could subsequently adopt many of the phenotypes typical of ES cell
differentiation (Terada et al.,
2002). A similarly low frequency of fusion (one event per
105 CNS cells) has also been reported when mouse CNS cells (also
genetically altered) were mixed with ES cells, and in this case the derived
hybrid cells were able to show multilineage potential when injected into
blastocysts, most prominently into liver
(Ying et al., 2002
).
Before one rushes headlong to the conclusion that all apparently
transdifferentiated cells are heterokaryons, and although one should look at
the genotype of cells claimed to have been generated from tissue of another
type, several observations nevertheless strongly indicate that the phenomenon
of adult stem cell plasticity is not dead in the water far from it. It
is interesting to look at epithelial tissue from mothers of male offspring.
Post-partum exacerbation of thyroiditis is sometimes observed and could be due
to transplacentally acquired foetal cells that cause an alloimmune disease
previously regarded as an autoimmune disease
(Srivatsa et al., 2001).
Particularly noteworthy was one female patient with clusters of fully
differentiated thyroid follicular cells bearing one X and one Y chromosome; of
course the source of the transdifferentiated cells was the foetus rather than
a deliberate transplant, but nevertheless no follicular cells were XXXY, which
suggests cell fusion was not responsible for the phenomenon, even when foetal
cells were the source. In a similar vein, an investigation by fluorescence in
situ hybridisation (FISH) of the karyotype of male donor peripheral blood stem
cells that had apparently transdifferentiated into epidermal, hepatic and
gastric mucosal cells in human female recipients clearly demonstrated the
presence of only one X and one Y chromosome
(Korbling et al., 2002
).
Likewise, Okamoto et al. (Okamoto et al.,
2002
) have found no evidence for cell fusion being responsible for
the apparent engraftment and differentiation of bone marrow cells into mucosal
epithelial cells throughout the gastrointestinal tract of human female
recipients of male bone marrow. They noted sustained engraftment over many
months/years, up to 13% (much higher than the reported fusion rates with ES
cells) of colonocytes being marrow-derived shortly after the development of
GVHD (graft versus host disease), but more significantly Y-chromosome-positive
epithelia did not stain more intensely than other epithelial cells with
4,6-diaminidino-2 phenylindole (DAPI): these observations argue against cell
fusion being the mechanism. Moreover, male recipients of male marrow had only
one Y chromosome. Of course, the detection of polyploidy by in situ
hybridisation is not without its problems, not least of which is the fact that
not all chromosomes can be visualised in a tissue section of finite thickness.
Perhaps a better approach is that of Kleeberger et al.
(Kleeberger et al., 2002
), who
examined liver chimerism in liver allografts by PCR analysis of a highly
polymorphic tetranucleotide repeat marker at the human ß-actin-related
pseudogene. Using laser-assisted microdissection of small areas of pure
hepatocytes and bile duct cells, they did indeed find that almost all samples
displayed the genotype of both donor and recipient, thus suggesting
engraftment from an extrahepatic source. However, cell fusion could not be
excluded since the samples contained more than one cell, but if single cells
could be captured this approach could settle the cell fusion issue.
Although not directly disproving that cell fusion happens in vivo, a number
of in vitro observations also strongly point to the plasticity of adult cells.
For example, Catherine Verfaillie and colleagues
(Schwartz et al., 2002;
Jiang et al., 2002a
;
Jiang et al., 2002b
) have
isolated so-called multipotent adult progenitor cells (MAPCs) from mesenchymal
cell cultures obtained from human and rodent bone marrow. These MAPCs are
capable of in excess of a hundred population doublings and can be induced to
differentiate not only into mesenchymal lineages but also into endothelia,
neuroectoderm (neurons, astrocytes and oligodendrocytes) and endoderm
(hepatocytes). Moreover, the group has provided evidence of function as well
as phenotype, allaying the fears expressed by some commentators that many
transdifferentiated cells merely take on the appearance rather than the
function of their new creation.
In the rat, a population of bone-marrow-derived hepatocyte stem cells
(BDHSC) has been identified on the basis of being
ß2-microglobulin negative and Thy-1 positive
(ß2m-/Thy-1+)
(Avital et al., 2001). These
cells are more numerous in damaged liver and express albumin, even in the bone
marrow. After these BDHSCs are co-cultured with cholestatic hepatocytes
(separated by a semi-permeable membrane, so no fusion could occur) they
differentiate into hepatocytes and are able to metabolise ammonia into urea as
efficiently as existing hepatocytes; prior co-culture with healthy hepatocytes
is not sufficient to achieve this. So here we have another situation where
fusion could not be responsible for the transdifferentiation. Likewise,
pancreatic cells can readily differentiate into their embryological cousins,
the hepatocytes, both in vitro (Shen et
al., 2000
) and in vivo
(Krakowski et al., 1999
), and
no fusion or heterokaryon formation has been described. Moreover, in the in
vitro study, the induced transdifferentiation commonly occurred directly
without cell cycle traverse and involved the vast majority of a pure
population of exocrine pancreatic cells which could not involve fusion
with another cell type.
Cells derived from sorted bone marrow cells can also apparently
differentiate into cardiomyocytes. In female mice, direct injection of
Lin- c-kit+ bone marrow cells (from
male EGFP transgenic donors) into the contracting area bordering an
experimental infarct results in more than half the infarcted area being
colonised by donor cells within nine days
(Orlic et al., 2001). Since
cardiomyocytes are cells that have a minimal regenerative capability, it is
extremely unlikely that cell fusion has occurred and bestowed the resultant
hybrids with hitherto-unrecognised migratory/proliferative powers.
In a `proof of principle' demonstration of the potential therapeutic use of
bone marrow, mice with a metabolic liver disease have been cured
(Lagasse et al., 2000). Female
mice lacking the enzyme fumarylacetoacetate hydrolase (FAH-/-, a
model of fatal hereditary tyrosinaemia type 1), a key component of the
tyrosine catabolic pathway, can be rescued biochemically by 106
unfractionated bone marrow cells that are wildtype for FAH. Moreover, only
purified HSCs
(c-kithiThyloLin-Sca-1+) are
capable of this functional repopulation, as few as 50 of these cells being
capable of hepatic engraftment when haematopoiesis is supported by
2x105 FAH-/- congenic adult female bone marrow
cells. The salient point to arise from this powerful demonstration of the
therapeutic potential of bone marrow cells was that, although the initial
engraftment was low (approximately one bone marrow cell for every million
indigenous hepatocytes), the strong selection pressure exerted thereafter on
the engrafted bone marrow cells resulted in their clonal expansion to occupy
almost half the liver. This positive selection was achieved by withdrawal of
2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC), a compound
that blocks the breakdown of tyrosine to fumarylacetoacetate (FAA) in the
FAH-deficient mice. In the absence of NTBC, FAA accumulates and destroys the
hepatocytes; thus the ensuing regenerative stimulus promotes the growth of the
engrafted cells. Furthermore, in the absence of NTBC, no engraftment is seen
(Wang et al., 2002
). Likewise,
bone-marrow-derived hepatocytes can be selectively expanded if they are
engineered to overexpress Bcl-2, and then the indigenous cells are targeted
for destruction by an anti-Fas antibody
(Mallet et al., 2002
). One
could also add that, if fusion were responsible for all these observations
made in the liver, then clearly these hybrids would have a selective growth
advantage, turning unhealthy hepatocytes into metabolically competent
hepatocytes and would not negate the therapeutic potential of bone marrow
cells in the liver. Expressing a similar sentiment, Blau has suggested that if
cell fusion is responsible for the apparent reprogramming of certain adult
cells then there is something `exciting' about rescuing damaged cells through
fusion, with, for example, bone-marrow-derived cells providing a healthy and
entire genetic complement, even one that has been manipulated for gene therapy
(Blau, 2002
).
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The case against adult stem cell plasticity |
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A recent study using a similar protocol to that emplyed by Bjornson and
colleagues rigorously tested the haematopoietic potential of murine
neurosphere cells and was unable to find any evidence of haematopoietic
differentiation in a large group (108) of sublethally irradiated mice each
transplanted with 106 neurosphere cells, which suggested that
haematopoietic potential was not a general property of neural stem cells
(Morshead et al., 2002).
However, Lako et al. have found that cells surrounding the murine vibrissa
(whisker) follicle (dermal sheath cells) and also dermal papilla cells can
exhibit both in vitro haematopoietic potential and reconstitute the bone
marrow of lethally irradiated mice and may be passaged into secondary
recipients (Lako et al.,
2002
). Moreover, the authors considered that contamination of the
dermal-derived cells by haematopoietic cells was not responsible for their
haematopoietic potential, unlike another recent report that found that the
haematopoietic potential of muscle cells was due to haematopoietic cell
contamination of the donor muscle cells
(McKinney-Freeman et al.,
2002
). From a similar tissue source, and supporting the concept of
adult stem cell plasticity, multipotential cells have been isolated from
rodent and human skin, specifically from the dermis, and named skin-derived
precursors (SKPs) (Toma et al.,
2001
). These cells can undergo multiple rounds of cell division in
vitro and can be directed to undergo differentiation along neuroectodermal
lines (neurons and glial cells) or mesodermal lines (adipocytes and smooth
muscle) so no cell fusion here! These cells are distinguishable in
their behaviour from plastic-adherent bone marrow mesenchymal cells, and
apparently clonally derived spheres of these cells could generate all the
above lineages so perhaps they are equivalent?
Another controversial issue centres on the claim that just one single cell
from a male mouse bone marrow population (lineage-depleted and enriched for
CD34+ and Sca-1+ by in vivo homing to the bone marrow)
can, when injected into female recipients along with 2x104
female supportive haematopoietic progenitor cells, give rise to a spectrum of
epithelial cells: at 11 months a surprisingly high proportion of type II
pneumocytes were Y chromosome positive, although fewer Y-chromosome-positive
cells were seen in other tissues for example, 2% were
cytokeratin-positive in the skin (Krause
et al., 2001). The high level of lung engraftment was attributed
to lung damage caused by either the irradiation to eradicate endogenous bone
marrow to facilitate bone marrow transplantation or viral infection in the
temporarily immunosuppressed animals. Although the experiments are not
directly comparable, the observations of Wagers at al. led the authors to
speculate that `transdifferentiation of circulating HSCs is an extremely rare
event if it occurs at all' (Wagers et al.,
2002
)! In one approach, they transplanted single GFP-marked HSCs
into lethally irradiated nontransgenic recipients and, although
GFP+ HSCs colonised the bone marrow, no significant contribution
was made by these cells to epithelia. The other approach involved the
long-term study of parabiotic pairs between GFP+ mice and wild-type
mice, and once again significant chimerism was observed in the bone marrow but
not in other organs.
A third area where apparently conflicting observations have been made
concerns the ability of bone marrow to contribute to neural tissue. For
example, Mezey and colleagues, studying homozygous PU.1 mutant female mice
(PU.1 is a transcription factor required for the histogenesis of six of the
haematopoietic lineages) rescued these mice with a life-saving bone marrow
transplant from male wild-type donors and found that up to 4.6% of cells in
the CNS were Y chromosome positive and that up to 2.3% of Y-positive cells
possessed the neuronal markers NeuN and neuron-specific enolase (NSE)
(Mezey et al., 2000). By
contrast, Goodell and colleagues (Castro et
al., 2002
) found no neuronal differentiation in eight lethally
irradiated recipients of 2x103 SP cells from ROSA26 donors or
in twelve recipients of 2x106 whole bone marrow cells, even
though some of the recipients in both groups had a neuronal injury. What are
we to make of these discrepancies? It is difficult to say, but these are
isolated examples, and in each case the experimental conditions were not
identical.
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Conclusions |
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Of course, it is one thing for a circulating cell to engraft in another
organ and assume some or all of the phenotypic traits of that organ
(transdifferentiation the acquisition of a new phenotype), but it is
quite another for one to claim that the engrafted cell has become a local stem
cell in its new niche. So while a scattering of engrafted, apparently
transdifferentiated cells in no way establishes that these cells are capable
of robust clonal expansion in their new environment, and indeed this is what
is observed in the majority of recently published papers, it should not be
taken as a criticism. As we have noted, significant clonal expansion requires
the presence of a persistent selection pressure strongly favouring the
engrafted cells (Lagasse et al.,
2000; Wang et al.,
2002
).
The demonstration of engrafted cells becoming stem cells within their new
location would, ideally, require the isolation and transplantation of single
cells that self-renew and produce a family of descendents that eventually
become fully functional. However, some commentators have added that this
phenomenon should be shown to occur `naturally' (without intervening culture)
in organs not forced to undergo organ degeneration before accepting that stem
cells jump a lineage boundary (Anderson et
al., 2001). Clearly, it is difficult to track cells without
intervention, and most of the studies to date involve damage consequent upon
ablation of bone marrow by irradiation or chemical means, or the traumas of
surgery and rejection, where organs have been transplanted and then studied
some time later. A counter argument is that a degree of organ damage is
essential to allow transdifferentiation or stem cell plasticity to take place
at recognisable levels. It may be that migration of bone marrow stem cells
throughout the body acts essentially as a back-up system that can in
extremis augment an organ's intrinsic regenerative capacity. As Jonas
Frisen has eloquently reiterated (Holden
and Vogel, 2002
), the `no alteration in culture' postulate is only
relevant if the goal is to study normal physiology, but if you are studying
what is possible then it is absolutely OK to culture.
Finally, stem cell plasticity is encountered in other situations:
disturbances in the local stem cell microenvironment occur commonly in vivo,
resulting in major switches in tissue phenotype metaplasias
(Tosh and Slack, 2002)
and even more extremes of stem cell plasticity must occur when animals are
reproductively cloned by somatic cell nuclear transfer. Of course, nothing is
really new; scholars of Icelandic literature (The Prose Edda, written in 1220)
will be aware that Thor knew that he could regenerate his slaughtered goats by
placing their intact bones (with the bone marrow) on their skins (Thor's
Journey to Utgard).
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