Division of Pediatric Hematology-Oncology Children's
Hospital and Dana Farber Cancer Institute Harvard Medical School Howard Hughes
Medical Institute Boston, MA 02115
orkin@rascal.med.harvard.edu
The extraordinary plasticity of tissue stem cells, such as the ability
of blood stem cells to differentiate into liver, would intrigue even the ancient
alchemists. Recent discoveries also force us to rethink cell lineage relationships
and expand the potential for cell-based therapies (pages
1229−1234).
CLASSIC EXPERIMENTS IN the 1950s demonstrating that introducing the nuclei
of specialized cells into oocytes could redirect cell fate provided stunning
support for extraordinary reversibility of the differentiated state1,
2.
The birth in 1997 of Dolly, the celebrated sheep derived from mammary gland
cells of a Finn Dorset ewe, affirmed this principle3 and established
the field of animal cloning. Researchers now realize that developmental plasticity
is not restricted to an embryonic environment. A particularly salient example
of this is provided by Lagasse et al.4 in this issue.
The authors report that hematopoietic stem cells (HSCs) contribute to hepatocytes
and can be used to correct an animal model of severe liver disease, hereditary
tyrosinemia type I (ref. 4). These and other findings5,
6,
7,
8,
9,
10,
11 challenge conventional ideas of organ development
and blur distinctions between tissues derived from the three germ layers (ectoderm,
mesoderm and endoderm). In so doing, they lay a foundation for new forms of
cell therapy of human disease.
Stem cells have two main responsibilities12: They generate
additional stem cells, and they give rise to differentiated progenitor cells
that commit to development along specific pathways. Perhaps more is known
about HSCs than about any other stem cell compartment in vertebrates. HSCs
sustain blood formation throughout the life of the individual and also are
the vehicle for reconstitution of the entire hematopoietic system after bone
marrow transplantation, a procedure of unquestioned clinical utility. Researchers
have worked for more than two decades to define cell surface and internal
markers of both human and mouse HSCs, allowing their separation from the committed
progenitors in bone marrow13.
Until recently, most researchers believed that stem cells were restricted
in their potential to an individual organ system. For example, HSCs of bone
marrow and satellite cells of muscle would only be able to yield additional
blood and muscle cells, respectively. The idea of tissue-restricted stem cells
is compatible with progressive 'pruning' of options during development and
the origin of tissues from specific germ layers. However, in vivo observations
made by Lagasse et al. and others4,
5,
6,
7,
8,
9,
10,
11
demonstrate the extraordinary plasticity of 'tissue stem cells' (stem cells
derived from a specific organ) (Fig. 1). Perhaps most
impressive is the broad developmental capacity of neural stem cells14,
15,
16.
Hematopoietic stem cells in bone marrow, which differentiate into blood
cells, also give rise to vascular (blood vessel) and muscle cells, as well
as hepatocytes (liver). In addition, tissue stem cells of the vascular system
and muscles contribute to blood production in vivo. Neural stem cells
show broad developmental potential, contributing to the development of blood
as well as to all germ layers in chimeric embryos.
The interrelationship between cells of different tissues can be reconciled
with their embryological origins. For example, mesoderm gives rise to blood
cells, muscle and endothelial cells. Accordingly, progenitors common to blood
and vascular cells and bearing the vascular endothelial growth factor receptor
Flk-1 or surface marker CD34 have been identified in mice and humans17,
18. Bone marrow has been shown to contain myogenic progenitors
that contribute to regenerating muscle in mice5. Subsequent
studies have shown that some HSCs, characterized by a distinctive profile
of Hoechst 33342 staining (called the side population)19 are
the progenitors of muscle, rather than a muscle-committed cell residing in
the marrow environment6. Conversely, transplanted muscle-derived
cells with an side-population profile contribute to hematopoiesis7.
The in vivo conversion of cultured, clonal neural stem cells into
hematopoietic cells8 and the demonstration that adult neural
stem cells contribute to all germ layers of chimeric chick-mouse embryos9 are seemingly heretical and violate preconceptions about tissues
origins. Preliminary accounts of marrow-derived cells contributing to liver10,
11, a product of endoderm, are also directly relevant to the work
of Lagasse et al.4 The findings of Lagasse et al.4 build on this framework in two ways. First they identified the bone
marrow-derived cells as HSCs, as defined by their surface markers (c-kit
highThylowLinnegSca-1+).
They also demonstrated the potential for therapeutic correction of a hepatic
enzyme deficiency, albeit in circumstances in which normal cells are selected
in the presence of an exogenously administered drug.
There are two possible mechanisms by which tissue stem cells may give rise
to differentiated cells characteristic of another organ. Stem cells obtained
from different sites might share properties and represent multipotent cells
that are set aside during development, perhaps in reserve for later use. Alternatively,
tissue-restricted stem cells found at different anatomical sites might bear
little immediate relationship to each other but have the ability to become
reprogrammed in vivo on demand.
At present, data are lacking to clearly discriminate between these different
routes to a common end. It seems highly unlikely, however, that all tissue-restricted
stem cells share the surface phenotype of HSCs (c-kithighThy
lowLinnegSca-1+). Nonetheless, the possibility
remains that the side-population phenotype, which is shared by the HSCs and
muscle-derived cells that contribute in vivo to muscle and blood, respectively,
is a 'signature' of a highly plastic stem cell.
By their design, most in vivo stem cell experiments have involved
substantial manipulation of recipient animals or the donor cells. For example,
animals typically have been prepared by irradiation or by induction of damage
to muscle or blood vessels. Moreover, the handling of donor cells seems to
influence outcome, as culture of muscle-derived progenitors augments hematopoietic
contribution6. More work is required to determine the mechanisms
by which different microenvironments can induce stem cells to develop along
different pathways. Similarly, it will be important to clarify whether stem
cells undergo trans-differentiation, as opposed to de-differentiation and
re-differentiation. In many reports of in vivo stem cell plasticity,
the identity of the contributing cell requires more in-depth analysis. The
study of Lagasse et al.4 is a notable step forward.
Despite uncertainty regarding the mechanisms underlying stem cell plasticity,
there is unlimited speculation regarding their clinical applications. Tissue
stem cells have been envisioned as a resource for restoring defective or damaged
organs. Their therapeutic potential may be greatly expanded by exploiting
gene transfer methods, perhaps ultimately overcoming obstacles to somatic
gene therapy. However, most of the evidence supporting the potential for stem
cell therapies has been obtained from experiments in mice. Of course, mouse
stem cells may differ from those of human origin in their capacity to be re-educated
in vivo. Nonetheless, the ability to derive hepatocytes from non-hepatic
adult stem cells in human bone marrow transplant recipients indicates that
observations made in mice may indeed translate to humans20.
The ability to turn blood into liver would be the envy of the alchemists
of former times. Turning stem cells into 'therapeutic gold' will probably
rest on our ability to identify the mechanisms by which tissue-derived stem
cells respond to environmental cues and execute new developmental decisions.
Manipulating cell fates in vitro is a challenging and important goal
for current research. Although the full developmental potential of tissue
stem cells remains to be discovered, we can be sure of one thing: More surprises
undoubtedly await stem cell researchers.
Briggs, R. & Kint, T.J. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl. Acad. Sci. USA38, 455–463 (1952).
Gurdon, J.B. in The Control of Gene Expression in Development (Clarendon Press, Oxford, 1974).
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Orkin, S.H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet.1, 57–64 (2000). | Article | PubMed | ISI | ChemPort |
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Doetsch, F., Caille, I., Lim, D.A., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell97, 703–716 (1999). | Article | PubMed | ISI | ChemPort |
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Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood87, 67–72 (1996). | PubMed | ISI | ChemPort |
Wood, H.B., May, G., Healy, L., Enver, T. & Morriss-Kay, G.M. CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis. Blood90, 2300–2311 (1997). | PubMed | ISI | ChemPort |
Goodell, M.A., Brose, K., Paradis, G., Conner, A.S. & Mulligan, R.C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med.183, 1797–1806 (1996). | Article | PubMed | ISI | ChemPort |
