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REVIEW ARTICLE
From the Albert Einstein College of Medicine, Bronx,
NY.
During the past few years an avalanche of papers
describing the conversion of transplanted bone marrow cells into
skeletal muscle, heart, liver, brain, and various epithelial tissues
suggested a surprising degree of hematopoietic stem cell plasticity.
For the clinician they raised the expectation that adult hematopoietic stem cells might one day become useful for tissue replacement therapies
and in ethically less controversial ways than embryonic stem cells. For
the developmental hematologist these findings were more incremental in
nature, because evidence accumulated over the last 2 decades indicated
that hematopoietic cells can be induced to convert from one lineage
into another. Although a number of excellent reviews have covered the
general topic of stem cell plasticity1-5 (also see
http://www.nih.gov/news/stemcell/scireport.html), none has
primarily focused on hematopoietic cells, and little has been written
about intrahematopoietic or "lineage" plasticity. The present
review aims to fill this gap. In the first part I will discuss the
capacity of cultured blood cells to transdifferentiate from one lineage
to another and present a model of how this might happen. In the second
part I will review experiments that show that bone marrow cells can
apparently turn into almost any tissue and discuss the question whether
or not the cells that "switch" represent bona fide hematopoietic cells. Current models of hematopoietic differentiation state that stem
cells become gradually restricted in their differentiation potential by
a succession of symmetric and asymmetric divisions. Each intermediate
progenitor and each monopotent precursor has a distinct gene expression
program that is established and maintained by specific combinations of
transcription factors and chromatin remodeling components. It is
generally assumed that once a cell commits to a given lineage and
acquires a defined phenotype, it can no longer change its fate.
However, as summarized in Table 1 and
Figure 1, and as will be elaborated in
the following section, there are numerous examples where seemingly
committed hematopoietic cells can be induced to convert into cells of
another lineage.
Switches between lymphoid and myeloid cells
In addition to the observed transition of B-lineage cells into
macrophages, one study reported a switch of B-lymphoid cells to
neutrophil granulocytes.9 While creating transgenic mouse lines involving the max gene, the authors obtained one line
(called max 41) that contained dramatically increased
numbers of granulocytes at the expense of B lymphocytes. Although this
unbalance per se does not imply an in vivo lineage switch, the
following experiments suggest that this is indeed the case. When max
41 was crossed with the Eu myc mouse, which has a propensity
to form pre-B cell lymphomas, animals were obtained that likewise
developed pre-B cell lymphomas but, in addition, contained elevated
levels of granulocytes. These lymphomas were transplantable and
generated in the recipient not only new lymphoma cells but also
granulocytes of donor origin. Transplantation experiments with cloned
pre-B-lymphoma cell lines derived from this cross showed that its
granulocytes contained the same pattern of immunoglobulin
rearrangements.9 The gene whose altered activity in the
max 41 mice facilitates the switch has not been reported so
far. It is also unclear whether or not a B lymphoid-to-granulocyte
switch occurs normally (see also below).
A surprising degree of plasticity was discovered in B-lineage
cells derived from Pax-5 knockout mice: on the one hand these cells
exhibit characteristics of pre-BI cells (B220+,
AA4.1+, c-Kitlow, SL chain+ but
CD19
Another series of experiments demonstrated that common lymphoid
progenitors (CLPs), can be reprogrammed to become
myelomonocytic.13 These experiments involved the analysis
of a transgenic mouse line that ectopically expresses the human IL-2
receptor All of the experiments discussed so far were performed with cells
that were either derived from lymphomas, transformed by an oncogene, or
altered by mutations. This raises the possibility that the observed
plasticity represents a phenomenon restricted to cells with altered
growth properties. However, recent work suggests it can also happen
with normal B-lineage cells, at least in culture. Thus, CD19 antigen,
DJ rearrangement-positive, B220 If B cells can be switched to become macrophages, can such a switch
also be observed in the opposite direction? In the cell system where
this was studied the answer seems to be yes. The experiment consisted
in characterizing the pattern of gene expression of macrophagelike
variants obtained from the pre-B lymphoma cell line 70Z/3, and restore
the down-regulation of transcription factors that are suspected to play
a role in commitment. Of the 3 transcription factors known to be
required for progression through the early stages of B-cell
development, E2A, EBF, and Pax5,12 E2A and EBF were
completely absent in the macrophage variant, whereas expression of
Pax-5 was reduced. Enforced expression of the E12 encoding
E2A gene caused a decreased adherence of the cells,
down-regulation of Mac-1 and of c-fms, and induction of a
number B lineage-specific genes, that included the IL7R, EBF,
and RAG1 genes, and the ability to form The examples of lineage plasticity discussed between B cells and
myelomonocytic cells suggest a close developmental relationship. This
might reflect the fact that they arise from a common progenitor in
fetal liver (together with T cells, NK cells, and dendritic cells)17,18 and that they both require the transcription
factor PU.1 for commitment (for reviews, see Singh et al19
and Orkin20). In addition, lin There is also an example of a possible developmental connection between
T-lineage cells and macrophages. The thymus is known to harbor
macrophages that act as scavengers to remove dead cell bodies generated
during T-cell development. Although the developmental origin of these
macrophages is obscure, a recent study suggests that they arise locally
through the differentiation of immature T cells. Thus, culturing of a
subset of purified pro-T cells in the presence of conditioned medium
from a thymic stromal cell line generated functional macrophages. This
lymphoid-to-myeloid transition could also be observed in the presence
of a combination of IL-6, IL-7, and macrophage colony-stimulating
factor (M-CSF; CSF-1), but at a lower frequency.22
Lineage switches within the myeloid/erythroid compartment
Similar observations were made in other systems and in normal, cultured
cells. PU.1 has been reported to induce the expression of macrophage
markers in a murine erythroid cell line.34 Conversely, GATA-1 confers an erythroid/megakaryocytic phenotype in myeloid cells.32,35,36 These cells up-regulate a number of
erythroid/megakaryocytic genes, such as c-mpl, EPO
receptor, a-globin, EKLF, NF-E2, and ets-1,
while down-regulating myelomonocytic genes, such as mac-1 and c-fms.36,37 Finally, a recent study suggests
that primary myelomonocytic progenitors can be reprogrammed into
erythroid cells by enforced expression of GATA-1. As in the MEP system, eosinophils (and basophils) were also observed (C. Heyworth and T. Enver, personal communication, September 2001).
As can be seen from the summary in Figure 1, not all possible
transitions between lineages have been described. Whether this simply
reflects limited number of attempts or lack of appropriate conditions,
or whether certain switches are not possible, remains to be seen.
Probably, however, the facility with which cells from one lineage can
transdifferentiate into another depends on how closely related they are
to each other and how much their transcription factor machinery overlaps.
Selection of a few or instruction of many?
Does transdifferentiation imply a reversal of differentiation?
Despite their apparent capacity to retrodifferentiate, there is no
evidence that any of the lineage switches described involve a detour
via an earlier progenitor. For example, if it is assumed that a B
cell-to-myeloid switch involves the formation of a lymphohematopoietic progenitor, then cells from lineages other than macrophages, such as T
cells or erythroid cells, should be generated. However, this has not
been described. Likewise, the GATA-1-induced expression of eosinophil
markers in myeloid cells is not preceded by the up-regulation of MEP
cell markers.32,33 Finally, the CSF-1-induced transition
of Pax-5 Do intrahematopoietic lineage switches occur in vivo? Can lineage switches also be shown to occur in vivo, under physiologic conditions, or are they restricted to experimental manipulations in cell culture? The existing knowledge, accumulated over many years of research, would suggest that the answer is no. Thus the concept that cells may "change their mind" during differentiation flies in the face of the belief that hematopoiesis is a linear process with multilineage progenitors becoming restricted in a stepwise but irreversible fashion. The following examples illustrate this point: (1) The fact that lethally irradiated mice receiving transplants of short-term repopulating (STR) cells do not survive suggests that these cells cannot convert into long-term repopulating (LTR) cells in vivo. (2) The existence of progenitors that are apparently exclusively committed to the production of restricted progeny (CLPs, common multipotent progenitors [CMPs], granulocyte/macrophage progenitors [GMPs], MEPs, B- and T-cell progenitors44,45) would also argue that, if lineage switching occurs, it must be at low frequencies. (3) A similar argument can be made for the high degree of congruency in the phenotype of individual colonies observed after replating single cells from colony "starts."46 However, none of these approaches rule out the possibility that lineage switching occurs in vivo, but at frequencies too low to be detected with technologies used so far. Finally, even if lineage switching does not occur in unperturbed animals, it is still possible that it happens under conditions of stress, such as during immunization, inflammation, or pathogen infection.How can the question of in vivo plasticity best be approached
experimentally? Lymphoid-to-myeloid cell transitions offer a seemingly
straightforward approach because immunoglobulin and T-cell receptor
gene rearrangements are irreversible and nonlymphoid cells of this
origin should be irreversibly marked. For example, the transition from
CD19+ cells into macrophages (and B cells),14
if it happens in vivo, should result in a fraction (if small) of
resident monocyte/macrophages that contain DJ rearrangements. However,
this has (not yet) been reported. In practice, Southern blots may not
be sensitive enough to detect minor fractions of cells with
rearrangements, and PCR techniques require cell populations that are
100% pure, which is not always easy to achieve. Because no DNA
rearrangements occur in cells of other lineages, it is even more
difficult to demonstrate transitions between nonlymphoid cells and
other cell types. Here a recently developed approach might be
informative. It uses bacterial recombinase (Cre-LoxP or FLP-FRT) to
mark the DNA of cells that express a given lineage marker. Briefly,
mice are created in which the expression of the recombinase gene, say
Cre, is driven by a cell type-specific marker, say the B
cell-specific CD19 gene. These mice are then crossed to a
reporter mouse that contains a DNA cassette framed by LoxP sites,
sequences that are recognized by the bacterial recombinase. In this
cross, Cre removes the cassette in all CD19-expressing B cells and this
change is retained in all non-B-cell derivatives. Conveniently,
removal of the cassette can be visualized at the single cell level by
There may be an example of an in vivo lineage switch after all,
involving the formation of dendritic cells. Transplantation experiments
showed that CMPs give rise to myeloid type (Mac-1+,
CD8 A model of how hematopoietic cells might switch lineage How can the process of lineage switching be explained at the molecular level? Before speculating about possible mechanisms, it is useful to briefly recapitulate current ideas about how blood cell lineages become specified during the differentiation of multipotent progenitors. One popular model proposes that hematopoietic stem cells "sneak preview" a large range of lineage-restricted genes and specific gene expression programs become dominant after that in a random process of gene fluctuation.40,56 This concept is based on the finding that hematopoietic multipotent progenitors express low levels of genes characteristic for different lineages, such as globin and myeloperoxidase as well as diverse cytokine receptor genes,57 and that Pax-5 / pre-BI cells
express genes from nonlymphoid lineages.11 However, extrinsic events such as cytokine signaling might also play a role in
commitment,39 with both intrinsic and extrinsic processes probably reinforcing each other's effects. Ultimately, the phenotype of a cell is established and maintained by combinations of
transcription factors that regulate lineage-specific gene
expression programs.
How do ectopically expressed transcription factors manage to reprogram
cells in a reversible fashion? Here I will discuss a model, derived
from studies with the E26 system described earlier, postulating that
the relative excess of a key transcription factor over another can lead
to the "controlled collapse" of a cell's phenotype. This involves
both the suppression of the cell's gene expression program and the
activation of novel genes, in a fashion that can be compared to a
reversible chemical reaction, with different phenotypes representing
"energy sinks." As summarized in Figure 4C, MEPs, eosinophils, and
myeloblasts can be converted into one another by inappropriate
transcription factor expression. Lineage transitions can be induced
according to a simple code that defines cell identity: high GATA-1 plus
FOG-1 specifies MEPs; moderate GATA-1 plus C/EBP
What is the ground state of transcription factor expression in erythroid/myeloid progenitors and how does commitment get started? The idea is that multipotent progenitors express both GATA-1 and PU.1 and that the latter is expressed at relatively low levels.45 External signaling events or intrinsic fluctuations or both may tip the balance between the 2 transcription factors, thus allowing the progenitors to differentiate along one or another pathway. This interpretation is supported by the observation that MEP cell clones can differentiate spontaneously into myeloblasts at low frequencies and that this transition can be accelerated by treatments that mimic growth factor receptor stimulation.24,29 Is the transcription factor cross-antagonism model more generally
applicable? Although a definitive answer is not yet in, a few more
examples can be cited. Within the E26 system, FOG-1 antagonizes C/EBP
expression, driving an eosinophil to MEP transition, and vice versa,
although a direct interaction of the 2 factors remains to be
demonstrated.20,33 The latter process may involve the
interruption by FOG-1 of an autoregulatory loop of
C/EBP The handful of transcription factors covered in this review are not the only players involved, and readers are referred to other reviews discussing additional factors (for myeloid/erythroid lineages, see Tenen et al,23 Yamanaka,74 Nagamura-Inoue et al75; for lymphoid lineages, see Rothenberg et al,76 Glimcher and Singh,77 Glimcher and Murphy78). In addition, transcription factors involved in lineage specification almost certainly do not act in simple 2-way combinations but are part of cell-specific transcription factor networks, where they participate in positive and negative cross-regulations at transcriptional and posttranscriptional levels. One can imagine that these networks have a 3-dimensional shape that changes as the cell's transcription factor composition is altered. Such "conformational changes," rather than being merely consequences of differentiation, might constitute a driving force during commitment.79 Other mechanisms, not involving direct transcription factor interactions, also play a role during hematopoietic lineage specification and transdifferentiation. Examples include competition for the general coactivators CBP/p30080-82 and histone-modifying factors that are involved in chromatin remodeling. These processes help to establish and stabilize the differentiated state.83
Until recently it has been widely assumed that there are 2 major
classes of stem cells: embryonic stem cells derived from early embryos,
able to replenish all cell types in the animal, and stem cells located
in various organs of the body, dedicated to the replenishment of
specific tissues, such as blood, muscle, and brain (for a review, see
Fuchs and Segre84). This assumption was shaken a few years
ago by the observation that bone marrow cells can differentiate into
muscle cells after transplantation,85 followed by reports
that cells derived from brain and muscle can fully reconstitute the
hematopoietic system of lethally irradiated mice.86-88 Are
all of these conversions due to the plasticity of hematopoietic cells?
It is particularly difficult to assess whether true conversions occur
from nonhematopoietic to hematopoietic tissues because hematopoietic
stem cells (HSCs), entering these tissues via the circulation, might
act as "contaminants." Indeed, recent experiments revealed that
skeletal muscle tissue contains multilineage hematopoietic progenitors
and LTR-HSCs. These cells were clearly derived from bone marrow because
HSCs recovered from the muscle of mice that were previously
reconstituted with marked donor cells were of donor
origin.89 In addition, cells in the skeletal muscle
capable of generating hematopoietic colonies and of hematopoietic
engraftment are CD45+, Sca-1+, whereas cells
that contribute to muscle cell formation after transplantation are
CD45 The remainder of this review will focus on conversions from
hematopoietic to nonhematopoietic tissues. The different types of
conversions that have been reported are summarized in Figure 7 and Table
2. Using mice transgenic for the
muscle-specific myosin light chain 3F promoter driving LacZ (MLC3F-lacZ
mice) as donors, Ferrari and coworkers injected bone marrow cells into leg muscles regenerating after chemical injury. When they analyzed muscle sections 2 to 5 weeks later they detected
Although the reported transitions of bone marrow-derived cells into muscle cells were unexpected, a series of papers describing conversions into epithelial cells were even more surprising. Several studies reported the formation of liver cells from transplanted bone marrow in mice,96,97 rats,98 and humans.99 Others suggested that bone marrow cells can turn into neuronal cells. Following publications describing donor-type microglia and astrocytes in mice that received bone marrow transplants,100,101 Mezey et al102 and Brazelton et al103 reported the detection of cells with neural markers in the brain PU.1 defective or irradiated recipients, respectively. However, these studies failed to demonstrate the formation of mature/functional neurons and their hematopoietic origin is also unclear. Finally, a recent paper described the in vivo conversion of bone marrow cells into epithelial cells of various organs in mice that underwent transplantation.104 This paper will be discussed in more detail below. Which of the bone marrow-to-nonblood cell conversions can be attributed to bona fide hematopoietic cells? If it is already difficult to rigorously establish hematopoietic cell plasticity using cultured cell lines, it is even more difficult to conclude that hematopoietic cells are plastic based on transplantation experiments. There is always the possibility that the bone marrow hosts a variety of dedicated tissue-specific stem cells, such as muscle stem cells, neuronal stem cells, and hepatic progenitors. The following requirements have to be met before concluding that a hematopoietic-to-nonhematopoietic transdifferentiation has been demonstrated ("the gold standard"): (1) Show that bone marrow cells purified on the basis of established cell surface markers cannot only reconstitute irradiated mice but can also participate in the formation of nonhematopoietic tissues. (2) Demonstrate that this can be done with a single cell or else clonal reconstitution of both types of tissues. (3) Demonstrate that the bone marrow-derived nonhematopoietic cells are differentiated and functional.Although there is (as yet) no evidence for the presence of dedicated
muscle, neuronal, or liver cell progenitors in the bone marrow, this
tissue is certainly heterogeneous and appears to contain various types
of hematopoietic as well as nonhematopoietic progenitors (Figure
8). Based on their long-term or
short-term repopulation capacity of lethally irradiated hosts, 2 types
of hematopoietic stem cells can be distinguished: LTR-HSCs and STR-HSCs (eg, see Lanzkron et al105). Both types of HSCs in the
mouse are Lin
In addition to hematopoietic cells, the bone marrow cavity probably
contains angiogenic precursors (also called endothelial progenitor
cells or angioblasts), which in humans are CD34+,
Kithigh, Flk-1+, Tie-2+, AC133.
Endothelial progenitor cells have been found in the
circulation111-113 and can be mobilized by
G-CSF.114 These cells, when transplanted, give rise to
mature endothelial cells in vessels and can be selected by adherence
and culture under endothelial conditions.114 However, some
of the selected cells might be of hematopoietic origin because human
monocytes cultured in the presence of angiogenic growth factors have
been shown to acquire properties of endothelial
cells.115-117 A third class of stem cells contained in the
bone marrow are mesenchymal stem cells (MSCs, also called stromal
cells) which are CD45 Which of the reported conversions of bone marrow to nonhematopoietic
cells involve bona fide hematopoietic progenitors, rather than
reflecting developmental potentials of other types of progenitors? Here
2 papers will discussed in some detail. In an elegant study, Lagasse et
al97 transplanted bone marrow cells from a mouse ubiquitously labeled with
That a single bone marrow-derived stem cell can differentiate not only
into blood cells but also into a wide variety of epithelial cells is
indicated by work of Krause et al.104 In this study, the
authors enriched Lin Although experiments discussed strongly indicated the potential
of bona fide hematopoietic cells to convert into various types of
epithelial cells, this is less clear for the reported conversions into
muscle, endothelial cells, and brain cells. Considering that the bone
marrow contains various types of stem cells (Figure 8), it is possible
that the donor-derived muscle and endothelial cells observed after bone
marrow transplantation85,93,94 originate from mesenchymal
stem cells and angiogenic precursors, respectively. Likewise, the
neuronal cells observed in the transplantation experiments of Mezey et
al102 and Brazelton et al103 might have arisen
from mesenchymal stem cells. As an alternative to this more
conventional interpretation, it has recently been postulated that a
universal adult stem cell exists that comes in different
coats.5 In this extreme view the various types of stem
cells residing in the bone marrow, brain, heart, and muscles are
considered to represent different states of a universal adult
progenitor whose phenotype is defined by its local environment. These
stem cells can move from one tissue into another via the circulation
and are more plastic in early than in more differentiated
stages.5 Accepting this view, which might be called the
"Heisenberg principle of stem cell biology," the issue of stem cell
plasticity becomes almost semantic. Taking it to the limit, the only
way to prove plasticity would be in instances where already
differentiated cells can be shown to transdifferentiate into other,
well-defined cell types. That this is a possibility is illustrated by
examples from the world outside Blood. Myocytes have been
shown to "transdifferentiate" into proliferating stem cells during
tissue regeneration in amphibians127 or following
expression of the msx-1 gene,128;
C/EBP Do hematopoietic-to-nonhematopoietic conversions occur normally during embryonic development and in adult animals? Almost all reported conversions between hematopoietic and nonhematopoietic cells in vivo were carried out by forced tissue relocations in irradiated or injured animals. For example, the experiments demonstrating a conversion from hematopoietic to epithelial cells were performed with irradiated animals. Irradiation, on the other hand, has been shown to destroy not only hematopoietic but also endothelial and epithelial tissues.131 It is therefore important to know whether such tissue conversions also occur under physiologic conditions. This question seems irrelevant if the ultimate purpose is to use somatic stem cells in tissue replacement therapies. However, knowledge about existing cellular processes might well be useful in guiding the development of tissue replacement protocols. In principle, tissue conversions might occur during embryonic development, involving the migration of hematopoietic cells from the yolk sac, aorta/gonad/mesonephros (AGM), or fetal liver to the anlagen of nonhematopoietic organs. For example, it has been reported that macrophages migrate from the yolk sac into the neural fold area,132 possibly seeding the brain with microglia (strictly speaking, however, this would not represent a "switch," because microglia are phagocytic cells that express macrophage markers). So far, there are no reports showing a reprogramming of hematopoietic cells nonhematopoietic tissues during development, but some evidence suggests a developmental flow in the opposite direction, from endothelial to hematopoietic cells. Thus, early blood cell progenitors share a number of markers with endothelial cells133 and colony assays indicate the existence of a common endothelial/blood cell progenitor, the "hemangioblast."134 In addition, endothelial cells within the chick embryonic aorta labeled with a vital stain or with a LacZ-encoding retrovirus were shown to develop into blood cells.135,136 These experiments were interpreted as evidence for cells with a dual hematopoietic and endothelial differentiation potential. However, it is also conceivable that hemangioblasts/hematopoietic cells can originate from fully functional endothelial cells,133 such as through local signaling events that induce their transdifferentiation. This issue might be hard to resolve. Clearly, there is a close relationship between endothelial cells and cells from other mesodermal lineages, a concept strengthened by the recently described "meso-angioblast" discovered in birds. This embryonic aorta-derived stem cell, which expresses CD34, c-Kit, and Flk-1, is capable of giving rise to vessels, blood, cartilage, bone, as well as to smooth, skeletal, and cardiac muscle cells (G. Cossu, personal communication, February 2002).
The cell culture experiments reviewed here leave little doubt about the intrinsic plasticity of hematopoietic cells, with cells from almost any lineage being capable of switching into cells of another lineage. The switches appear to represent true transdifferentiation events, with cells moving backwards as well as sideways within the differentiation tree. Reprogramming is initiated either by extrinsic or intrinsic events that result in changes in transcription factors active in commitment and maintenance of lineage-specific gene expression programs. The transcription factors involved in commitment appear to have a dual role; they not only set up novel gene expression programs through transcriptional activation but also extinguish old programs through inactivating interactions with an antagonistic transcription factor. Whether committed hematopoietic cells can "change their mind" during normal development and in adult animals, perhaps in situations of stress, is an area that needs to be explored. Knowledge of such mechanisms may shed new light on the evolution of the hematopoietic system, its homeostasis, and its adaptation to pathogen invasion during innate immunity. The interpretation of the hematopoietic-to-nonhematopoietic cell conversions described is complicated by the fact that the bone marrow cavity not only hosts bona fide hematopoietic precursors but 2 or more additional types of stem cells. In most studies it is therefore difficult to conclude with certainty that a blood-to-nonblood cell switch has actually occurred. Thus, although it is clear that hepatocytes and other epithelial cell types can derive from transplanted hematopoietic stem cells, the conversion to skeletal and cardiac muscle, neuronal cells, macroglia, and vessels is less clear and could involve mesenchymal stem cells as well as angiogenic precursors. And, as for the intrahematopoietic lineage conversions, it remains to be seen whether blood-to-nonblood conversions occur during normal embryonic development or even as an ongoing process in adults. Another interesting area for future investigations is to define stem cell niches, and how different microenvironments influence the developmental potential of bone marrow-derived stem cells. Some of the reports covered in this review have suggested that hematopoietic stem cells can serve as an alternative to embryonic stem cells for tissue replacement after injury or disease, such as stroke and heart infarct, Parkinson disease, cystic fibrosis, muscular dystrophy, and congenital liver diseases. Because of the vast amount of knowledge accumulated in their handling for the purpose of transplantation and their relatively easy isolation, they would indeed be an ideal source for organ repair and reconstitution. The clinical prospects for the use of adult hematopoietic stem cells for these purposes largely depends on whether it will be possible to develop protocols that increase the tissue conversion frequencies and noninvasive strategies that involve the mobilization of bone marrow progenitors. Clearly, the field is still in its infancy and basic research will have to go hand in hand with clinical research to explore the suitability of hematopoietic stem cells for tissue replacement therapies.
I would like to thank Todd Evans, Gordon Keller, Kelly McNagny, Fabio Rossi, Gwen Randolph, and members of the Graf lab for discussions and suggestions.
Submitted September 20, 2001; accepted December 28, 2001.
Supported by NIH grants 1 RO1 CA89590-01 and 1 RO1 N543881-01.
Reprints: Thomas Graf, 1300 Morris Park Ave, Bronx, NY 10461; e-mail: graf{at}aecom.yu.edu.
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B. Jacquelin, T. Kortulewski, P. Vaigot, A. Pawlik, G. Gruel, O. Alibert, P. Soularue, C. Joubert, X. Gidrol, and D. T.-L. Roux Novel pathway for megakaryocyte production after in vivo conditional eradication of integrin {alpha}IIb-expressing cells Blood, September 15, 2005; 106(6): 1965 - 1974. [Abstract] [Full Text] [PDF]
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 H. K. Haider and M. Ashraf Bone marrow stem cell transplantation for cardiac repair Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2557 - H2567. [Abstract] [Full Text] [PDF]
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 T. N. Taghon, E.-S. David, J. C. Zuniga-Pflucker, and E. V. Rothenberg Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling Genes & Dev., April 15, 2005; 19(8): 965 - 978. [Abstract] [Full Text] [PDF]
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M. Stadtfeld and T. Graf Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing Development, January 1, 2005; 132(1): 203 - 213. [Abstract] [Full Text] [PDF]
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 N Dainiak and R C Ricks The evolving role of haematopoietic cell transplantation in radiation injury: potentials and limitations Br. J. Radiol., January 1, 2005; Supplement_27(1): 169 - 174. [Abstract] [Full Text] [PDF]
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 J.-P. Lalonde, R. Lim, E. Ingley, P. A. Tilbrook, M. J. Thompson, R. McCulloch, J. G Beaumont, C. Wicking, H. J. Eyre, G. R. Sutherland, et al. HLS5, a Novel RBCC (Ring Finger, B Box, Coiled-coil) Family Member Isolated from a Hemopoietic Lineage Switch, Is a Candidate Tumor Suppressor J. Biol. Chem., February 27, 2004; 279(9): 8181 - 8189. [Abstract] [Full Text] [PDF]
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L. Bruno, R. Hoffmann, F. McBlane, J. Brown, R. Gupta, C. Joshi, S. Pearson, T. Seidl, C. Heyworth, and T. Enver Molecular Signatures of Self-Renewal, Differentiation, and Lineage Choice in Multipotential Hemopoietic Progenitor Cells In Vitro Mol. Cell. Biol., January 15, 2004; 24(2): 741 - 756. [Abstract] [Full Text] [PDF]
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 S. Rutella, G. Bonanno, M. Marone, D. de Ritis, A. Mariotti, M. T. Voso, G. Scambia, S. Mancuso, G. Leone, and L. Pierelli Identification of a Novel Subpopulation of Human Cord Blood CD34-CD133-CD7-CD45+Lineage- Cells Capable of Lymphoid/NK Cell Differentiation After In Vitro Exposure to IL-15 J. Immunol., September 15, 2003; 171(6): 2977 - 2988. [Abstract] [Full Text] [PDF]
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 J. S. Forrester, M. J. Price, and R. R. Makkar Stem Cell Repair of Infarcted Myocardium: An Overview for Clinicians Circulation, September 2, 2003; 108(9): 1139 - 1145. [Full Text] [PDF]
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 M. Korbling and Z. Estrov Adult Stem Cells for Tissue Repair -- A New Therapeutic Concept? N. Engl. J. Med., August 7, 2003; 349(6): 570 - 582. [Full Text] [PDF]
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S. A. Perez, P. A. Sotiropoulou, D. G. Gkika, L. G. Mahaira, D. K. Niarchos, A. D. Gritzapis, Y. G. Kavalakis, A. I. Antsaklis, C. N. Baxevanis, and M. Papamichail A novel myeloid-like NK cell progenitor in human umbilical cord blood Blood, May 1, 2003; 101(9): 3444 - 3450. [Abstract] [Full Text] [PDF]
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A. A. Hofling, C. Vogler, M. H. Creer, and M. S. Sands Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplantation model of lysosomal storage disease Blood, March 1, 2003; 101(5): 2054 - 2063. [Abstract] [Full Text] [PDF]
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K. M. McNagny and T. Graf E26 leukemia virus converts primitive erythroid cells into cycling multilineage progenitors Blood, February 1, 2003; 101(3): 1103 - 1110. [Abstract] [Full Text] [PDF]
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K. Akashi, X. He, J. Chen, H. Iwasaki, C. Niu, B. Steenhard, J. Zhang, J. Haug, and L. Li Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis Blood, January 15, 2003; 101(2): 383 - 389. [Abstract] [Full Text] [PDF]
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 D. Orlic, J. M. Hill, and A. E. Arai Stem Cells for Myocardial Regeneration Circ. Res., December 13, 2002; 91(12): 1092 - 1102. [Abstract] [Full Text] [PDF]
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N.I. Moldovan and K. Havemann Transdifferentiation, a Potential Mechanism for Covering Vascular Grafts Grown Within Recipient's Peritoneal Cavity With Endothelial-Like Cells Circ. Res., August 9, 2002; 91 (3): e1 - e1. [Full Text] [PDF]
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K. McNagny and T. Graf Making Eosinophils Through Subtle Shifts in Transcription Factor Expression J. Exp. Med., June 3, 2002; 195(11): F43 - F47. [Full Text] [PDF]
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 M. ANGHELINA, A. SCHMEISSER, P. KRISHNAN, L. MOLDOVAN, R.H. STRASSER, and N.I. MOLDOVAN Migration of Monocytes/Macrophages In Vitro and In Vivo Is Accompanied by MMP12-dependent Tunnel Formation and by Neovascularization Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 209 - 216. [Abstract] [PDF]
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Top
Introduction
Lineage switches within the...
chain. When CLPs from this mouse were cocultured
with OP9 stromal cells plus IL-7 they differentiated into B cells and
NK cells. However, additional treatment with human IL-2 induced the
formation of granulocytes and macrophages (no such cells developed when
CLPs from control mice were grown under the same conditions). The
signaling pathways required for the establishment of the 2 myelomonocytic lineages seem to be separable: When introduced into CLPs
by retroviral infection, a mutant 
light chain
in response to mitogens. Similar, but less dramatic, changes were
observed after enforced expression of the EBF gene,
suggesting that it acts downstream of E2A.
to a lack of neutrophil and eosinophil granulocytes;
and ablation of C/EBP
in
the bone marrow or after the cells home to epithelial tissues? Is
tissue injury necessary for engraftment in epithelial tissues (see also
below), and what are the homing clues?