1. Clinical review
The therapeutic potential of stem cells from adults
Ingrid Kuehnle, Margaret A Goodell
Adult stem cells seem to have the capacity to “transdifferentiate” into cells of many different tissue
types; now further work is needed to establish their role in treating degenerative diseases
Center for Cell and The discovery of adult tissue specific stem cells, such as
Gene Therapy,
Baylor College of
haematopoietic stem cells, which have the ability to Summary points
Medicine, Houston, “transdifferentiate” into other tissues, has generated
TX 77030 USA much excitement among cell biologists and transplant
Ingrid Kuehnle Pluripotent embryonic stem cells divide
clinicians. It opens new avenues for basic biological
assistant professor indefinitely and ostensibly generate all cell types
Margaret A Goodell
research by using stem cells from adults as an alterna-
assistant professor tive to stem cells from embryos. It also carries Stem cells from adults regenerate their resident
Correspondence to: important implications for the treatment of many liver, tissue but may have broader potential for
M A Goodell heart, and neurodegenerative diseases. Despite strong differentiation (multipotential)
goodell@bcm. evidence that multipotent stem cells (stem cells with
tmc.edu
the potential to differentiate into several cell types) Further work must establish the broad
BMJ 2002;325:372–6 reside in many adult organs and can be manipulated in differentiation and functional potential of stem
ways that may confer a therapeutic advantage, several cells from adults
questions remain to be addressed before the
development of clinical applications. We review recent Clinical utility of all stem cells awaits further
findings on the “plasticity” of adult stem cells to adopt validation and development
a fate different from their originally intended one, and
we discuss the potential clinical importance of this
finding. We also point out some directions for research marrow and stem cells. By contrast, despite the well
in the future. documented presence of stem cells in several mature
tissues, including muscle, brain, skin, liver, and
Methods mammary gland, they remain poorly defined and
underexploited in the clinic.1 Recent reports suggest
We searched Medline with both general keywords such that some of these stem cells can differentiate outside
as “stem cells,” “stem cell plasticity,” “adult stem cells,” of their tissue of origin (box and fig 1).
and “embryonal stem cells” and with more specific
terms such as “haematopoietic, hepatic or muscle stem
cells,” “Parkinson’s disease,” and “osteogenesis imper- Adult stem cells versus embryonic
fecta.” We also cite published and unpublished data stem cells
generated in our laboratory.
Since the isolation of stem cells from human embryos
two years ago, the prospect of using such cells to
Adult stem cells reconsidered
After development of the embryo most tissues are
Muscle Endothelial cells
fully differentiated, and further growth or repair of stem cells Blood vessels
damaged sites is undertaken by stem cells residing in
particular tissues. Adult stem cell populations have
been most thoroughly characterised in mouse and Muscle Bone marrow
Resident Haematopoietic cells, osteoblasts,
human bone marrow, where they continuously Liver
haematopoietic endothelial cells, fibroblasts,
replenish the differentiated cells of the peripheral stem cells mesenchymal cell precursors
blood lost through attrition. From studies of the
haematopoietic system it has been possible to define a
Central nervous system
stem cell as a cell with the capacity to self renew and to
generate cells of multiple diverse lineage within the
tissue in which the stem cell resides. The ability of the Fig 1 Possible pathways for differentiation in adult stem cells. Cells
within bone marrow may give rise to tissues such as endothelial
haematopoietic stem cells within bone marrow to give cells, liver, muscle, and neurones (red arrows). Alternatively
rise to all blood elements has been extensively haematopoietic stem cells in muscle or muscle stem cells in bone
exploited in the clinic for transplantation of bone marrow give rise to respective progeny (blue arrows)
372 BMJ VOLUME 325 17 AUGUST 2002 bmj.com

2. Clinical review
haematopoietic system after bone marrow transplanta-
Recent reports of potential plasticity of tion, and haematopoietic cells infiltrated all tissues. The
stem cells investigators therefore had to distinguish between
donor blood cells and donor cells that had become
The following reported experiments involved something else, such as hepatocytes. The most striking
transplantation of marked donor cells into whole
suggestion of stem cell plasticity was published in 1998
animals or directly into injured tissue and examination
of the recipient tissue for incorporation of the marked by an Italian group, which found that genetically
donor derived cells marked bone marrow cells from a mouse can migrate
Whole bone marrow reportedly generated: to sites of muscle injury and participate in muscle
Skeletal muscle2 regeneration, albeit at low efficiency.2 The implication
Cardiac muscle3 of this and similar studies performed with whole bone
Liver4–6
marrow—that the diverse donor cell types observed
Endothelial cells7
Brain8–10 after transplantation could all be derived from the
Muscle reportedly generated: haematopoietic system—captured the imagination of
Bone marrow11 12 13 researchers in tissue specific stem cells. It seemed that
Neural stem cells reportedly generated: given the appropriate environmental signals, adult
Blood14 cells derived from bone marrow have the capacity to
Skeletal muscle15 transdifferentiate into cells of many different organs,
Multiple embryonic tissues16
Enriched or purified haematopoietic stem cells
including liver hepatocytes, endothelial cells, and even
reportedly generated: neurones.
Skeletal muscle11 Two studies found that transplanted bone marrow
Cardiac muscle17 18 19 cells from adults could migrate into the brain and dif-
Endothelial cells17 ferentiate into cells expressing proteins specific for
Liver hepatocytes and bile duct20 neuronal cells.8 9 These findings suggest that cells con-
Multiple epithelial tissues21
tained within the bone marrow of the adult
transdifferentiated and assumed a neuronal fate. The
flaw in this interpretation is that besides haematopoi-
generate cells and tissues for cell therapy has etic stem cells, whole bone marrow contains a
stimulated much scientific and public interest. The spectrum of diverse cell types (for example, differenti-
stem cells are obtained from the inner cell mass of the ated haematopoietic cells, osteoblasts, endothelial
blastocyst (fig 2). As numerous studies with their mouse cells, fibroblasts, mesenchymal precursors that can dif-
counterparts have shown, the stem cells from human ferentiate into cartilage, bone, and fat23 24), which are
embryos are inherently primitive, can proliferate transferred to the recipient and which could
indefinitely, and have the capacity to generate all cell participate in the apparent differentiation events of
types of the adult.22 Yet because the embryo is non-haematopoietic origin.
destroyed to isolate the cells, a host of ethical issues has
deeply divided researchers and politicians alike.
Some researchers argue that stem cells derived
Turning blood into muscle, liver,
from adults have sufficient developmental potential
and brain
that they can be substituted for stem cells from the To garner support for the hypothesis that stem cells
embryo in therapeutic situations, without any appreci- from the haematopoietic system are capable of
able loss of regenerative efficacy. Others contend that participating in the differentiation into diverse tissue
the extensive capacity of adult stem cells to types, several groups have transplanted purified cells
differentiate has not been proved and that their capac- in a variety of settings. Gussoni and others
ity proliferation is more limited than that of embryonic transplanted several thousand haematopoietic stem
stem cells, so they may not provide a long term source cells from male mice into female mdx mice, a model of
of progenitor cells to replace tissue lost to chronic dis- Duchenne muscular dystrophy.11 They were able to
ease. Clearly there is a need to rigorously evaluate track the fate of the transplanted cells by detecting the
claims of differentiation “plasticity” of adult stem cells Y chromosome with fluorescent in situ hybridisation.
and their long term therapeutic potential. The donor cells efficiently replenished the bone mar-
row of the recipients as expected, and cells from the
males expressing dystrophin were found at low levels
Evidence for stem cell plasticity
in host muscle fibres, indicating differentiation of the
The first suggestion that stem cells from one tissue of
an adult could generate cells of an unrelated tissue
came from studies of whole bone marrow transplanta-
tion in humans and animal models, in which the trans-
planted cells could be distinguished from the
recipient’s tissues by using conventional histological
techniques. Examination of several different organs of
the recipient showed the presence of cells derived from
the donor in tissues other than the blood, including
endothelial, skeletal, and cardiac muscle cells, liver oval
cells, hepatocytes, and cells of the central nervous Fig 2 (Left) Embryonic stem cells from mouse (Wright Giemsa). Large pale staining cell
system.2–9 22 All of these studies were technically difficult (upper right) is either a stromal cell, with which these cells were grown, or a differentiated
because the donor cells formed most of the daughter of an embryonic stem cell. (Right) Haematopoietic stem cells from mouse
BMJ VOLUME 325 17 AUGUST 2002 bmj.com 373

3. Clinical review
transplanted cells into muscle. As in previous What does the future hold for adult stem
studies,evidence of the ostensibly multipotent capacity cells of non-haematopoietic origin?
of haematopoietic stem cells was based on the
Haematopoietic stem cells can be isolated prospec-
examination of tissues with markers specific for that
tively by using combinations of surface markers, but
tissue, such as dystrophin in skeletal muscle, and
such strategies have not yet been exploited for stem
markers that distinguish resident cells from those of
cells specific for other organs. These are usually identi-
the donor. Because of the low level of engraftment and
fied by their anatomical location or by markers associ-
the lack of clinically evident weakness in the mdx mice,
ated with their tissue progenitor cells. Surface markers
it was not possible to assess the contribution of the that may be specific for adult stem cells are beginning
engrafted cells to cardiac function or muscle strength. to emerge and may soon allow a prospective
Analogous studies in our laboratory have shown evaluation of the transdifferentiative capacity of adult
that the progeny of transplanted haematopoietic stem stem cells of non-haematopoietic origin.
cells can also contribute to the repair of capillaries
(fig 3) and cardiomyocytes in a mouse model of Muscle stem cells
coronary artery infarction.17 Orlic and others also Skeletal muscle contains a potent myogenic stem cell
observed that when a population enriched in haema- population with the ability to regenerate muscle in
topoietic stem cells was injected directly into injured vivo. Our group transplanted mice with a crude
mixture of muscle derived mononuclear cells that dis-
hearts it could participate in the regeneration of
played the hallmarks of primitive haematopoietic stem
cardiac muscle, leading to an apparent improvement
cells. The transplanted cells gave rise to all haemato-
of cardiac function.18 They also recently showed that
poietic cells and possessed the capacity for self renewal,
treatment of mice with granulocyte colony stimulating
as shown by their ability to contribute to blood
factor, which is known to mobilise stem cells from
production after serial transplantation into secondary
bone marrow into blood, protected mice from some of recipients.12 This suggested that the haematopoietic
the damage of induced myocardial infarction.19 This activity of muscle originated from myogenic stem cells
suggested that the increased number of circulating that had switched fate on introduction to the regener-
stem cells was protective, perhaps through engraft- ating bone marrow, which had been highly stimulated
ment of cells into the heart, although this was after lethal irradiation. Equally tenable interpretations
not shown. were that a progenitor common to both the haemato-
Lagasse and others were the first to provide strong poietic and the myogenic lineage was present in the
support for the concept of transdifferentiation at a muscle specimens or, more likely, that true haemato-
functional level by using small numbers of purified poietic stem cells were present in muscle, for unknown
stem cells. They showed that as few as 30 highly reasons. Recent data from Ogawa’s and our own group
purified haematopoietic stem cells injected into mice suggest that bone marrow derived haematopoietic
with an inducible lethal hereditary liver disease, tyrosi- stem cells contained within the muscle are responsible
naemia type 1, could repopulate the haematopoietic for the haematopoietic potential initially thought to be
system as well as differentiate into hepatocytes and res- derived from muscle cells.25 26 This finding emphasises
cue the animals from hepatic failure and death.20 the need for caution when interpreting the results of
Although these studies support the idea of the dif- studies in transdifferentiation.
ferentiation “plasticity” of adult stem cells, definitive Neuronal stem cells
proof is still lacking. In all of these experiments multi- Over the past two decades the transplantation of cells
ple cells were transplanted, from between 30 and or stem cells has emerged as an attractive approach to
several thousand. Even with as few as 30 highly purified the restoration of function in neurodegenerative
cells, multiple stem cell types could be present—for diseases such as Parkinson’s and Alzheimer’s. Implan-
example, a progenitor of both haematopoietic and tation of dopaminergic neuroblasts, from embryos,
non-haematopoietic origin—accounting for differen- which are already committed by fate into the brains of
tiation into multiple tissue types. Definitive proof patients with Parkinson’s disease has yielded promis-
requires experiments to show that a single stem cell ing results, including clinical improvement in some
can differentiate into more than one tissue type. patients.27 28 The problems with this strategy—need for
embryonic tissue, localised delivery of dopaminergic
cells, and limited graft survival—have impeded its
broader use. Neuronal stem cells have also been
isolated from the brains of embryos and adults.29 30
Adult neural stem cells have the potential to differen-
tiate into multiple cell types of the brain, mainly
oligodendrocytes, astrocytes, and neurones, giving
them a major therapeutic advantage over committed
progenitor cells such as those used in transplants for
Parkinson’s disease. Moreover, these neural stem cells
Fig 3 Enriched haematopoietic stem cells engrafted in endothelial layer of blood vessels. may be multipotent: when injected into blastocysts of
(Left) lacZ-positive cells derived from stem cells (arrow). (Right) Endothelial cells (arrow). mice they contributed to multiple types of tissues in
Haematopoietic stem cells were purified from Rosa26 transgenic mice, which express the lacZ
the embryos.16 One study reported the generation of
transgene ( galactosidase) widely, and transplanted into the bone marrow of irradiated
recipients. Several months after transplantation the tibialis anterior was injured by injection of blood from neuronal stem cells when transplanted
cardiotoxin. Two weeks later, cryosections were made and stained with X-gal, to detect into lethally irradiated recipients, but this has not yet
galactosidase, and anti-PE-CAM1 antibody, to detect endothelial cells been reproduced.14 These neuronal stem cells have
374 BMJ VOLUME 325 17 AUGUST 2002 bmj.com

4. Clinical review
also been observed to generate skeletal muscle when
cultured with a cell line capable of differentiating into Additional educational resources
muscle or when injected into regenerating muscle.15
Further experiments are needed to determine Useful publications
whether the transdifferentiative potential of neuronal Lagasse E, Shizuru JA, Uchida N, Tsukamoto A,
Weissman IL. Toward regenerative medicine. Immunity
stem cells resides in specific clones or defines this cell
2001;14:425-36
type in general and whether these properties will be Very good overview of the properties and potential of
generalisable to neural stem cells in humans. haematopoietic stem cells
Blau HM, Brazelton TR, Weimann JM. The evolving
concept of a stem cell: entity or function? Cell
Recent clinical observations 2001;105:829-41
Provides historical account of plasticity of stem cells
Although most published information on adult stem
from adults
cells draws heavily from studies with animal models, Wulf GG, Jackson KA, Goodell MA. Somatic stem cell
there is increasing clinical evidence to support the plasticity: current evidence and emerging concepts.
concept of stem cell transdifferentiation. Theise and Exp Hematol 2001;29:1361-70
others examined the livers of patients who received Comprehensive review of the specialty of stem cells
either bone marrow from someone of the opposite sex from adults, with summary of published data
or liver transplants. In both cases the authors found Lachmann P. Stem cell research—why is it regarded as
a threat? EMBO Rep 2001;2:165-8
hepatocytes and cholangiocytes from the opposite sex, An investigation of the economic and ethical
suggesting that a circulating bone marrow cell could arguments made against research with stem cells from
home to and transdifferentiate in the liver.6 Horwitz human embryos
and others showed engraftment of donor osteoblasts
Useful websites
and enhanced bone formation after bone marrow
National Institute of Health Stem Cell Primer
transplantation in children with the most severe form (www.nih.gov/news/stemcell/primer.htm)
of osteogenesis imperfecta, a genetic disorder of colla- Defines pluripotent stem cells, how they are derived,
gen production.31 The patients also showed major and why they are important to science and for
clinical benefits, including fewer fractures and advances in health care. Also defines stem cells from
increased growth velocity. The authors concluded that adults
functional mesenchymal progenitor cells residing in Report on stem cell research from the American
Association for the Advancement of Science
the bone marrow compartment were responsible for
(www.aaas.org/spp/dspp/sfrl/projects/stem/main.htm
the changes, although part of the therapeutic effect and www.aaas.org/spp/cstc/issues/stemcells.htm)
may have derived from haematopoietic stem cells with Discussion of scientific and ethical issues and policies
the capacity for transdifferentiation. surrounding stem cell research
St Jude’s Children’s Hospital (www.stjude.org/)
Conclusions Recent trials of bone marrow transplantation and
Stem cells derived from bone marrow, whether mesenchymal progenitor cell therapy in osteogenesis
imperfecta
multipotent haematopoietic stem cells or other tissue
National Institutes of Health (www.ninds.nih.gov/
specific stem cells resident in the bone marrow, have a parkinsonsweb/nigral.htm)
major advantage over stem cells from other organs: Recent trials of fetal tissue transplantation in
they are well defined, easy to isolate, and can be Parkinson’s disease
injected systemically, reaching other tissues through
the bloodstream. Moreover, transplantation of bone
marrow or haematopoietic stem cells leads to
chance or do they reflect a genetic programme that can
induction of donor tolerance, permitting transdifferen-
be activated by specific signals?
tiation or transplantation of other tissue specific stem
As studies are published, some of the earlier results
cells from the same donor without the need for
are being questioned. Do some of the reported obser-
prolonged immunosuppression of the recipient. None
vations of transdifferentiation represent events of cell
the less, the transdifferentiation events described in
fusion, as recently suggested for bone marrow and
most of these studies were rare, even under extreme
neural progenitor cells?32 33 Are there other potential
selective pressure. Do such events occur simply by
explanations for this apparently unorthodox behav-
iour of stem cells? Before adult stem cells are used
therapeutically in patients with degenerative disorders
Key progress needed in research into plasticity of the liver, heart, or brain, the properties of such cells
of stem cells from adults must be characterised, the factors responsible for their
regulation defined, and functionality proved.
Proof that a single stem cell from an adult can
differentiate into more than one cell or tissue type MAG is a scholar of the Leukemia and Lymphoma Society of
Proof of functionality: that progeny of America. We thank Maryellen R Goodell for critical reading of
“transdifferentiated” adult stem cells functionally the manuscript and Kathyjo A Jackson for producing figure 3.
integrate in the new tissue Competing interests: None declared.
Proof of functional benefit in non-autochtonous tissue
Improvements in efficiency of engraftment and 1 Lagasse E, Shizuru JA, Uchida N, Tsukamoto A, Weissman IL. Toward
regenerative medicine. Immunity 2001;14:425-36.
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A memorable patient
The headache and the rabbi
“The sudden onset of severe headache, in someone shouldn’t wait, which is what GPs usually do, but just
who doesn’t usually get headaches, especially a young get her into hospital as soon as possible.”
person. . . .”—the professor’s words, as best as I recall. The next day, I helped him with the removal of a
A woman in her mid-30s accompanied her mother deep seated arteriovenous malformation that had been
to my surgery one afternoon. The appointment was for leaking. The patient’s recovery was uncomplicated.
the mother, who asked if, instead, I could attend to the I was therefore surprised when she returned a few
daughter, who had a severe headache and didn’t weeks later: “I want to see you again, because I’ve got
normally get headaches. that same headache.” This time, the computed
She said that the headache had started suddenly that tomogram showed an abscess at the site of the excised
morning. Asked what she was doing at the time, she vascular anomaly. At a repeat performance of the
said that she was at the children’s school’s speech day. operation, we removed a 7-8 mm diameter ball of
Which school? “You know, the one on the hill.” bacteroides pus. She has had no trouble since.
This reply made me suspicious, as there were four When I meet her now, 20 years later, at the local
schools on the hill behind our surgery. I pressed her shopping centre she always gives me a hug and a kiss
further: “You know, the one my children go to.” and tells any surprised bystander, “He saved my life.” I
I tried another tack: “Who was giving the speech?” suppose I did, and, for a general practitioner in a fairly
“Rabbi Fraser.” pedestrian suburban practice, this was indeed a
Prime Minister Malcolm Fraser had many attributes, memorable experience.
but being rabbinical was not one of them. Settled on
Peter Arnold general practitioner
the diagnosis, I meticulously examined her nervous
system but found nothing else. I telephoned my usual We welcome articles of up to 600 words on topics such
neurosurgeon, who lived nearby and was, fortunately, as A memorable patient, A paper that changed my practice,
not working that afternoon. He was at my rooms My most unfortunate mistake, or any other piece
within half an hour, took the patient’s history, conveying instruction, pathos, or humour. If possible
conducted a more thorough examination but with the the article should be supplied on a disk. Permission is
same result, and took me to another room to discuss needed from the patient or a relative if an identifiable
his thoughts before telling the patient and her mother. patient is referred to. We also welcome contributions
“I’m always upset when GPs don’t get patients with for “Endpieces,” consisting of quotations of up to 80
subarachnoid haemorrhages to us early enough,” he words (but most are considerably shorter) from any
said, “but that’s what she has, even though there’s source, ancient or modern, which have appealed to the
nothing to confirm the diagnosis. I suppose we reader.
376 BMJ VOLUME 325 17 AUGUST 2002 bmj.com