J R Soc Med 2004;97:465-471
doi:10.1258/jrsm.97.10.465
© 2004 Royal Society of Medicine
Adult bone-marrow stem cells and their potential in medicine
H T Hassan MD PhD
M El-Sheemy MS PhD
Institute of Medical Sciences, University of Lincoln, UK
Correspondence to: Professor H T Hassan, Director, Institute of Medical
Sciences, University of Lincoln, Brayford Pool, Lincoln LN6 7TS, UKE-mail:
hhassan{at}lincoln.ac.uk
 |
INTRODUCTION
|
|---|
An area of research that today generates great optimism is the
use of stem
cells for therapy of human diseases. Much of the
excitement centres on
embryonic stem cells, but this approach
remains controversial for ethical
reasons; moreover, routine
clinical application of this strategy is many years
away. By
contrast, haematopoietic stem cells from adult bone marrow are
well
characterized and have long been used
therapeutically.
1 An
adult weighing 70 kg has a functional haematopoietic marrow
volume of about
1.75 L and upon increased demands such as infection
or haemorrhage it can
increase
sixfold.
1,2
No moral controversy
surrounds the use of these cells since they are either
autologous
or collected from a consenting donor. The potential applications
of
adult bone marrow cells have gained momentum with discoveries
relating to the
mesenchymal stem cell.
|
MESENCHYMAL STEM CELLS
|
|---|
Adult bone-marrow-derived mesenchymal stem cells (MSC) are capable
of
differentiation along several lineages (
Box
1).
3–15
They
are positive for CD29, CD44, CD105 and CD166, have a doubling
time of
about two days, expand in culture up to sixfold and
their biological functions
are not altered by
ageing.
3,15
Box 2 lists some of the
cytokine receptors expressed by these cells
and the cytokines produced. Their
features and properties are
closely similar to those of counterpart cells
isolated from
fetal blood, liver and bone in the first and second trimesters,
from
amniotic fluid and umbilical cord blood, and from adult peripheral
blood,
compact bone and adipose
tissue.
21–27
Moreover,
a CD133-positive subpopulation of these cells, which can be
expanded
under defined conditions for more than one hundred
population doublings
without telomere shortening or karyotypic
abnormality, has proved capable of
differentiation not only
into mesenchymal cell types (osteoblasts,
chondrocytes, adipocytes,
myocytes) but also into endothelium and cells with
neuroectodermal
phenotype and
function.
28–30
Previously, adult marrow-derived
stem cells were believed to yield a limited
number of cell types
whereas embryonic cells were totipotent. The discovery of
these
multipotent adult stem cells has clearly narrowed the gap: they
offer a
very promising and much more abundant potential resource
for therapy of
inherited or degenerative diseases and for repair
of tissues such as
cartilage, bone and myocardium.
View this table:
[in this window]
[in a new window]
|
Box 1. Differentiation potential of adult bone marrow mesenchymal stem
cells (from refs 3,
4,
5,
6,
7,
8,
9,
10,
11,
12,
13,
14,
15)
|
|
|
ADULT STEM CELL PLASTICITY
|
|---|
What is the mechanism of stem cell differentiation? When the
phenomenon was
first explored, the possibility of cell fusion
was mooted—that is,
hybridization with other cells rather
than true plasticity. Indeed, embryonic
stem cells were seen
to hybridize with brain cells to form tetraploid cells
with
pluripotent
character.
31
However,
in-vitro and
in-vivo studies
of adult bone marrow
stem cells suggest a rate of cell fusion
too low to account for the
transdifferentiation.
32
Moreover,
single euploid bone marrow MSC, never co-cultured with
tissue-specific
cells or embryonic cells, have been seen to differentiate into
cells
of the three germ
layers;
33 in
vivo, the use of bone marrow
cells selectively expressing the enhanced
green fluorescent
protein ruled out fusion as a mechanism for the generation
of
functional pancreatic islet beta
cells;
34 and
hepatocytes, cardiomyocytes,
and pancreatic and endothelial cells have been
described as
physiologically either diploid or
polyploid.
35–37
Certain
cytokines, including interleukins (IL) 1, 4, and 13, tumour
necrosis
factor alpha and interferon gamma, are involved in
the generation of normal
multinucleated cells such as osteoclasts
and Langhans giant
cells;
38–40
thus, observations suggesting
fusion of bone marrow cells with, for example,
Purkinje neurons,
cardiomyocytes and
hepatocytes
41 may
instead simply reflect
physiological polyploidy.
|
BIOLOGY OF ADULT MARROW MESENCHYMAL STEM CELLS
|
|---|
The direction in which bone marrow MSC differentiate is heavily
influenced
by cytokines (
Table 1). For
example, bone morphogenetic
protein 6 (BMP-6) not only influences
differentiation towards
chondrogenesis or osteogenesis but may also serve to
regulate
the bone marrow environment via the effects of IL-6 on haematopoiesis
and
osteogenesis.
50
Two possible mechanisms have been proposed for
a regulatory role of BMP-6 in
the human bone marrow microenvironment:
(i) it might enhance the osteoblastic
differentiation of human
MSC; or (ii) it might reduce the osteoclastic
differentiation
of haematopoietic marrow cells by decreasing interleukin-6
production
in bone marrow stroma. MSC coexpressing CD133 and fetal liver
kinase
1 generated endothelial cells in the presence of vascular endothelial
growth
factor, and functional hepatocytes in the presence of fibroblast
growth
factor-4 and hepatocyte growth
factor.
29,30
Also, MSC
coexpressing CD133, CD172 and nestin differentiated along a
neural
pathway in the presence of fibroblast growth factor or
retinoic acid plus
nerve growth
factor.
51,54
An MSC side-population
with high efflux of DNA binding dye and expressing CD90
(Thy1)
differentiated into mesangial renal
cells.
55
|
MIGRATION/MOBILIZATION OF ADULT MARROW STEM CELLS
|
|---|
In animal models, transplanted bone marrow cells have been detected
in
skeletal and cardiac
muscle,
56–58
vascular
endothelium,
58,59
liver,
60–62
lung,
gut and skin
epithelia,
62
pancreatic beta cell
islets,
34,63
renal
glomeruli,
14,55
and
neural
tissue.
33,64–69
When bone-marrow-derived MSC were
injected intracerebrally in
acid-sphingomyelinase-deficient
mice, the onset of neurological abnormalities
was delayed and
the animals lifespan was
extended.
70 Local
transplantation of
such cells is also reported to have regenerated
bone
71–73
and
myocardium.
74,75
It
is noteworthy that no donor-derived tumours have been seen in
these animal
models—whereas with transplantation of undifferentiated
embryonic stem
cells teratoma development has been
reported.
76 The
results also differ from those of undifferentiated embryonic
stem cell
transplantation in that engraftment and tissue-specific
differentiation are
achieved without pretransplantation measures
to induce differentiation down
the lineage desired. The ability
of marrow-derived cells to populate numerous
body tissues—bone,
liver, cardiac muscle, colon, skin—is well
shown in patients
who have received cells from gender-mismatched donors
(
Table
2).
77–84
A
postmortem study revealed donor-derived neurons in the hippocampus
and
cerebral cortex of brain samples from women who had received
bone marrow
transplants from
men.
85 Deductions
from such findings
must be qualified by the observation that women who have
carried
male fetuses may show long-term mosaicism with male cells;
nevertheless,
the weight of the evidence is that donor bone-marrow-derived
cells
can migrate and give rise to tissues belonging to all three
germ-cell
layers.
77–85
It is noteworthy that, in the transdifferentiation
of these adult marrow stem
cells, there was no evidence of cell
fusion.
77–85
Lately,
work in mice indicated that such cells participate in skin
regeneration
and reconstitution and promote wound
healing;
86–88
and
one research group reports a pilot study in three patients indicating
that
locally applied autologous bone marrow cells enhanced dermal
building and
closure of long-term non-healing
wounds.
89
View this table:
[in this window]
[in a new window]
|
Table 2. Migration of human adult bone marrow stem cells in gender-mismatched
bone marrow transplantation patients
|
|
|
CLINICAL STUDIES
|
|---|
In animal models of myocardial infarction, stem cells were reported
to
participate in repair whether injected locally or stimulated
in bone marrow by
use of stem cell factor (SCF) and
G-CSF.
90 In man, a
randomized placebo-controlled study revealed increased
coronary collateral
flow in patients treated with intracoronary
GM-CSF (molgramostim) followed by
two weeks of subcutaneous
administration.
91
In the past decade the use of G-CSF (filgrastim) has transformed the
treatment of cancer by facilitating marrow reconstitution after myeloablative
therapy. We must hope for a similar breakthrough in the management of coronary
heart disease.
In allogeneic transplantation, mesenchymal stem cells in bone marrow play a
key part in immunomodulation and the induction of tolerance. MSC suppress the
proliferation of T-lymphocytes induced by cellular or non-specific mitogenic
stimuli92 and
negatively influence B-cell
lymphopoiesis.93
Allogeneic/xenogeneic MSC transplants engraft in immunocompetent sheep and
non-human
primates.94–97
When a patient was treated, after myeloablation, with both haematopoietic stem
cells and cultured MSC from a mismatched donor, only grade I graft-versus-host
disease (GvHD) was
observed.98 That
MSC can not only reduce GvHD but also facilitate haematopoietic engraftment is
evidenced by the rapid haematopoietic recovery of patients with breast cancer
who received autologous blood stem cells together with culture-expanded MSC
after high-dose
chemotherapy.99 In
both clinical trials, MSC transplantation was well tolerated.
Osteogenesis imperfecta has been the focus of two studies in children.
Allogeneic MSC transplantation, leading to successful osteoblast engraftment
in 3 of 5 children with type III osteogenesis imperfecta, was associated with
a 44–77% increase in bone mineral content, improved linear growth and
reduced fracture
frequency.77,100
In another cohort of 6 children with type III osteogenesis imperfecta who had
received earlier bone marrow transplantation, MSC infusions from the original
donor resulted in a 50% improvement in their growth
velocity.101
Similar improvements were observed in children with metachromatic
leukodystrophy and Hurler’s syndrome after repeated allogeneic marrow
MSC
infusions.102
Ten clinical studies have been reported on the effects of autologous bone
marrow stem cell transplantation in patients with myocardial infarction or
ischaemic heart failure (Table
3).103–112
In three pilot studies, two of them randomized controlled trials, bone marrow
cells infused via a coronary catheter a few days after acute myocardial
infarction led to significant improvement in coronary flow reserve and left
ventricular ejection
fraction.104,105,111
In the remaining seven, marrow cells injected directly into the myocardium of
patients with chronic ischaemic heart disease yielded benefits in ejection
fraction and also angina
score.103,106–110,112
Despite the impressive safety record of all these pilot clinical trials,
the possibility of undesired differentiation into other tissues must be borne
in mind in monitoring of future studies.
|
THE FUTURE
|
|---|
In the next decade, the approaches discussed above will clearly
be
developed and refined. Further avenues will open up. For
example,
bone-marrow-derived cells expressing stem cell factor
have been shown to
initiate endogenous pancreatic tissue regeneration
in
mice.
113 If such
cells could be used as pancreatic beta islet
cell progenitors, there would be
scope for autologous transplantation
in patients with diabetes, avoiding the
need for the immunosuppression
necessary after allotransplantation and
circumventing the scarcity
of allogeneic material. Whereas the multipotent
adult dermal
stem cells from human scalp skin have shown mainly neural
differentiation,
suggesting a possible therapeutic role in neurodegenerative
diseases,
114,115
the
bone marrow MSC show strong orientation towards bone, cartilage,
endothelium
and cardiac muscle.
In conclusion, the existing medical uses of bone marrow are likely to
expand greatly with exploitation of the therapeutic potential of adult
mesenchymal stem cells, with their capacity for many lines of differentiation.
The next stage is to isolate the various subsets and investigate their
mechanisms of differentiation and homing to tissues. This work has vast
implications for human wellbeing, through cell and gene therapies, through
tissue engineering and through immunotherapy.
|
REFERENCES
|
|---|
- Hassan HT, Gutensohn K, Zander AR, Kuhnl P. CD34 positive cell
sorting and enrichment: applications in bloodbanking and transplantation. In:
Recktenwald D, Radbruch A, eds. Cell Separation: Methods and
Applications. New York: Marcel Dekker, 1998:283
–92
- Hassan HT, Zander AR. Stem cell factor as a survival and growth
factor in human normal and malignant hematopoiesis. Acta
Haematol 1996;95:257
–62[Medline]
- Sammons J, Ahmed N, El-Sheemy M, Hassan HT. The role of BMP-6, IL-6
and BMP-4 in mesenchymal stem cells-dependent bone development; effects on
osteoblastic differentiation induced by parathyroid hormone and vitamin
D3. Stem Cells Devel2004; 13:273
–80
- Awad HA, Butler DL, Boivin GP, et al. Autologous
mesenchymal stem cell-mediated repair of tendon. Tissue
Eng 1999;5:267
–77[Medline]
- Direkze NC, Forbes SJ, Brittan M, et al. Multiple organ
engraftment by bone marrow-derived myelofibroblasts and fibroblasts in bone
marrow-transplanted mice. Stem Cells2003; 21:514
–19[Medline]
- Ryden M, Dicker A, Gotherstrom C, et al. Functional
characterisation of human mesenchymal stem cell-derived adipocytes.
Biochem Biophys Res Commun2003; 311:391
–7[Medline]
- MacKay AM, Beck SC, Murphy JM, Barry FP, Chichester CO, Pettenger
MF. Chondrogenic differentiation of cultured human mesenchymal stem cells from
marrow. Tissue Eng1998; 4:415
–28[Medline]
- Wakitani S, Saito T, Caplan AI. Myogenic cells derived from rat
bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle
Nerve 1995;18:1417
–26[Medline]
- Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult
bone marrow stromal cells differentiate into neural cells in vitro.Exp Neurol2002; 174:11
–20[Medline]
- Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult
progenitor cell from bone marrow differentiate into functional hepatocyte-like
cells. J Clin Invest2002; 109:1291
–302[Medline]
- Reyes M, Dubek A, Jahagirdar B, Koodie L, Marker PH, Verfaille CM.
Origin of endothelial progenitors in human postnatal bone marrow. J
Clin Invest 2002;109:337
–46[Medline]
- Woodbury D, Schwartz EJ, Prockop DJ, Black IB. Adult rat and human
bone marrow stromal cells differentiate into neurones. J Neurosci
Res 2000;61:364
–70[Medline]
- Imai E, Ito T. Can bone marrow differentiate into renal cells?
Pediatr Nephrol2002; 17:790
–4[Medline]
- Lin F, Cordes K, Li L, et al. Hematopoietic stem cells
contribute to the regeneration of renal tubules after renal
ischemia–reperfusion injury in mice. J Am Soc
Nephrol 2003;14:1188
–99[Abstract/Free Full Text]
- Suva D, Garavaglia G, Menetrey J, et al.
Non-haematopoietic human bone marrow contains long-lasting pluripotential
mesenchymal stem cells. J Cell Physiol2004; 198:110
–18[Medline]
- Erices A, Conget P, Rojas C, Minguell JJ. Gp130 activation by
soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic
differentiation of human bone marrow-derived mesenchymal stem cells.
Exp Cell Res2002; 280:24
–32[Medline]
- Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for
molecular medicine in the 21st century. Trends Mol Med2001; 7:259
–67[Medline]
- De Ugarte DA, Alfonso Z, Zuk PA, et al. Differential
expression of stem cell mobilisation-associated molecules on multi-lineage
cells from adipose tissue and bone marrow. Immunol
Lett 2003;89:267
–71[Medline]
- Roufosse CA, Direkze NC, Otto WR, Wright NA. Circulating
mesenchymal stem cells. Int J Biochem Cell Biol2004; 36:585
–97[Medline]
- Bonnet D. Biology of human bone marrow stem cells. Clin
Exp Med 2003;3:140
–9[Medline]
- Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono T, Fisk
NM. Identification of mesenchymal stem/progenitor cells in human
first-trimester fetal blood, liver and bone marrow.
Blood2001; 98:2396
–402[Abstract/Free Full Text]
- Zvaifler NJ, Marinova-Mutafchieva L, Adams G, et al.
Mesenchymal precursor cells in the blood of normal individuals.
Arthritis Res2000; 2:477
–88[Medline]
- Zuk PA, Zhu M, Ashjian P, Benhaim P, Henrick MH, Fraser JK. Human
adipose tissue as source of multipotent stem cells. Mol Cell
Biol 2002;13:4279
–95
- Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative
sources of postnatal human mesenchymal stem cells: candidate MSC-like cells
from umbilical cord. Stem Cells2003; 21:105
–10[Medline]
- Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey
SA. Circulating skeletal stem cells. J Cell Biol2001; 153:1133
–40[Abstract/Free Full Text]
- in’t Anker PS, Noort WA, Scherjon SA, et al.
Mesenchymal stem cells in human second trimester bone marrow, liver, lung and
spleen exhibit a similar immunophenotype but a heterogeneous multilineage
differential potential. Haematologica2003; 88:845
–52[Abstract/Free Full Text]
- in’t Anker PS, Scherjon SA, Kleijburg-van der Keur C, et
al. Amniotic fluid as a novel source of mesenchymal stem cells for
therapeutic transplantation. Blood2003; 102:1548
–9[Free Full Text]
- Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM.
Purification and ex vivo expansion of postnatal human marrow
mesodermal progenitor cells. Blood2001; 98:2615
–25[Abstract/Free Full Text]
- Reyes M, Dubek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM.
Origin of endothelial progenitors in human postnatal bone marrow. J
Clin Invest 2002;109:337
–46
- Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult
progenitor cells from bone marrow differentiate into functional
hepatocyte-like cells. J Clin Invest2002; 109:1291
–302
- Ying QY, Nicols J, Evans EP, Smith AG. Changing potency by
spontaneous fusion. Nature2002; 416:545
–8[Medline]
- O’Malley K, Scott EW. Stem cell fusion confusion.
Exp Hematol2004; 32:131
–4[Medline]
- Jiang Y, Balkrishna N, Jahagirdar R, et al. Pluripotency
of mesenchymal stem cells derived from adult marrow.
Nature2002; 418:41
–9[Medline]
- Janus A, Holz GG, Theise ND, Hussain MA. In vivo
derivation of glucose-competent pancreatic endocrine cells from bone marrow
without evidence of cell fusion. J Clin Invest2003; 111:843
–50[Medline]
- Seglen PO. DNA ploidy and autophagic protein degradation as
determinants of hepatocellular growth and survival. Cell Biol
Toxicol 1997;13:301
–15[Medline]
- Brodsky V, Chernyaev AL, Vasilyeba IA. Variability of the
cardiomyocytes ploidy in normal human hearts. Virchow Arch B Cell
Pathol 1991;61:289
–94
- Lee GM, Rasch EM, Thornthwaite JT. Cytophotometric comparisons of
DNA levels in neuronal and glial cells of the cerebellum: a comparative study.
Cell Biochem Funct1984; 2:225
–36[Medline]
- Anderson JM. Multi-nucleated giant cells. Curr Opin
Hematol 2000;7:40
–7[Medline]
- Merkel KD, Erdmann JM, McHugh KP, Abu-Amer Y, Ross FP, Teitelbaum
SL. TNF-alpha mediates orthopaedic implant osteolysis. Am J
Pathol 1999;154:203
–10[Abstract/Free Full Text]
- Jimi E, Akiyama S, Tsurukai T, et al. Osteoclast
differentiation factor acts as a multifunctional regulator in murine
osteoclast differentiation and function. J Immunol1999; 163:434
–42[Abstract/Free Full Text]
- Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al.
Fusion of bone marrow-derived cells with purkinje neurones, cardiomyocytes and
hepatocytes. Nature2003; 425:768
–73
- Yoo JU, Barthel TS, Nishimura K, Solchaga L, Caplan AI, Goldberg
VM. The chondrogenic potential of human bone marrow-derived mesenchymal
progenitor cells. J Bone Joint Surg1998; 80A:1745
–67
- Sekiya I, Colter DC, Prockop DJ. BMP-6 enhances chondrogenesis in a
subpopulation of human marrow stromal cells. Biochem Biophys Res
Comm 2001;284:411
–18[Medline]
- Ogueta S, Munoz J, Obregon E, Delgado-Baeza E, Garcia-Ruiz JP.
Prolactin is a component of the human synovial liquid and modulates the growth
and chondrogenic differentiation of bone marrow derived mesenchymal stem
cells. Mol Cell Endocrinol2002; 190:51
–63[Medline]
- Coelho MJ, Fernandes MH. Human bone cell cultures in compatibility
testing. Part II: effect of ascorbic acid, beta-glycerophosphate and
dexamethasone on osteoblastic differentiation.
Biomaterials2000; 21:1095
–102[Medline]
- Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP. Osteogenic
differentiation of purified, culture-expanded human mesenchymal stem cells
in vitro. J Cell Biochem1997; 64:295[Medline]
- Sammons J, Ahmed N, Khokher MA, Hassan HT. Mechanisms mediating the
inhibitory effect of retinoic acid on haemopoietic stem cells in human
long-term bone marrow cultures. Stem Cells2000; 18:214
–19[Medline]
- Ahmed N, Khokher MA, Hassan HT. Cytokine-induced expansion of human
CD34 positive stem cell and CD34+CD41+ early megakaryocytic marrow cells
cultured on normal osteoblasts. Stem Cells1999; 17:92
–9[Medline]
- Ahmed N, Sammons J, Carson RJ, Khokher MA, Hassan HT. Effect of
bone morphogenetic protein-6 on haematopoietic stem cells and cytokine
production in normal human bone marrow stroma. Cell Biol
Int 2001;25:429
–35[Medline]
- Mbalaviele G, Jaiswal N, Meng A, Cheng L, Van Den Bos C, Thiede M.
Human mesenchymal stem cells promote human osteoclast differentiation from
CD34+ bone marrow hematopoietic progenitors.
Endocrinology1999; 140:3736
–3[Abstract/Free Full Text]
- Kim BJ, Seo JH, Bubien JK, Oh YS. Differentiation of adult bone
marrow stem cells into neuroprogenitor in vitro.NeuroReport2002; 13:1185
–8[Medline]
- Vogel W, Grunebach F, Messam CA, Kanz L, Brugger W, Buhring HJ.
Heterogeneity among human bone marrow-derived mesenchymal stem cells and
neural progenitor cells. Haematologica2003; 88:126
–33[Abstract/Free Full Text]
- Sanchez-Ramos JR, Song S, Cardoz-Paleaz F, et al. Adult
bone marrow stromal cells differentiate into neural cells in vitro.Exp Neurol2000; 164:247
–56[Medline]
- Reyes M, Verfaillie CM. Characterisation of multipotent adult
progenitor cells, a subpopulation of mesenchymal stem cells. Ann NY
Acad Sci 2001;938:231
–5[Medline]
- Ito T, Suzuki A, Imai E, Okabe M, Hori M. Bone marrow is a
reservoir of repopulating mesangial cells during glomerular remodelling.
J Am Soc Nephrol2001; 12:2625
–35[Abstract/Free Full Text]
- Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo
Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic
progenitors. Science1998; 279:528
–30
- Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells
regenerate infarcted myocardium. Nature2001; 410:701
–5[Medline]
- Jackson KA, Majka SM, Wang H, et al. Regeneration of
ischemic cardiac muscle and vascular endothelium by adult stem cells.
J Clin Invest2001; 107:1395
–402[Medline]
- Asahara T, Takahashi T, Masuda H, et al. Bone marrow
origin of endothelial progenitor cells responsible for postnatal
vasculogenesis in physiological and pathological neo-vascularisation.
Circulation Res1999; 85:221
–8[Abstract/Free Full Text]
- Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as
potential source of hepatic oval cells. Science1999; 284:1168
–70[Abstract/Free Full Text]
- Theise ND, Nimmakayalu M, Gardner R, et al. Derivation of
hepatocytes from bone marrow cells in mice after radiation-induced
myeloablation. Hepatology2000; 31:235
–40[Medline]
- Krause DS, Theise ND, Collector MI, et al. Multi-organ,
multi-lineage engraftment by a single bone marrow-derived stem cell.
Cell2001; 105:369
–77[Medline]
- Lee VM, Stoffel M. Bone marrow: an extra-pancreatic hideout for the
elusive pancreatic stem cell? J Clin Invest2003; 111:799
–801[Medline]
- Brazelton TR, Rossi FMV, Keshet GI, Blau HE. From marrow to brain:
expression of neuronal phenotypes in adult mice.
Science2000; 290:1775
–9[Abstract/Free Full Text]
- Kopen G, Prockop D, Phinney D. Marrow stromal cells migrate
throughout forebrain and cerebellum, and they differentiate into astrocytes
after injection into neonatal mouse brains. Proc Natl Acad Sci
USA 1999;96:10711
–16[Abstract/Free Full Text]
- Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning
blood into brain: cells bearing neuronal antigens generated in vivo
from bone marrow. Science2000; 290:1779
–82[Abstract/Free Full Text]
- Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg SW,
Dirnagl U. Neogenesis of cerebellar Purkinje neurons from gene-marked bone
marrow cells in vivo. J Cell Biol2001; 26:733
–8
- Azizi SA, Stokes D, Augelli BJ, Digirolamo C, Prockop DJ.
Engraftment and migration of human bone marrow stromal cells implanted in the
brains of albino rats—similarities to astrocyte grafts. Proc
Natl Acad Sci USA1998; 95:3908
–13[Abstract/Free Full Text]
- Schwarz EJ, Alexander GM, Prockop DJ, Azizi SA. Multi-potential
marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model
of Parkinson’s disease. Hum Gene Therapy1999; 10:2539
–49[Medline]
- Jin HK, Carter JE, Huntley GW, Schuchman EH. Intracerebral
transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient
mice delays the onset of neurological abnormalities and extends their life
span. J Clin Invest2002; 109:1183
–91[Medline]
- Pereira RF, O’Hara MD, Laptev AV, et al. Marrow
stromal cells as a source of progenitor cells for non-hematopoietic tissues in
transgenic mice with a phenotype of osteogenesis imperfecta. Proc
Natl Acad Sci USA1998; 95:1142
–7[Abstract/Free Full Text]
- Niedzwiedzki T, Dabrowski Z, Miszta H, Pawlikowski M. Bone healing
after bone marrow stromal cell transplantation to the bone defect.
Biomaterials1993; 14:115
–21[Medline]
- Kadiyala S, Jaiswal N, Bruder SP. Culture-expanded bone
marrow-derived mesenchymal stem cells regenerate a critical-sized bone defect.
Tissue Eng9197; 3:173
–85
- Pak HN, Qayyum M, Kim D, et al. Mesenchymal stem cell
injection induces cardiac nerve sprouting and increased tenascin expression in
a Swine model of myocardial infarction. J Cardiovasc
Electrophysiol2003; 14:841
–8[Medline]
- Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal
stem cell implantation in a swine myocardial infarct model: engraftment and
functional effects. Ann Thorac Surg2002; 73:1919
–25[Abstract/Free Full Text]
- Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al.
Embryonic stem cell lines derived from human blastocysts.
Science1998; 282:1145
–7[Abstract/Free Full Text]
- Horwitz EM, Prockop DJ, Fitzpatrick LA, et al.
Transplantability and therapeutic effects of bone marrow-derived mesenchymal
stem cells in children with osteogenesis imperfecta. Nat
Med 1999;5:309
–13[Medline]
- Theise ND, Nimmakayalu M, Gardner R, et al. Liver from
bone marrow in humans. Hepatology2000; 32:11[Medline]
- Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia
regenerated by bone marrow-derived cells in the human gastrointestinal tract.
Nat Med2002; 8:1011
–17[Medline]
- Korbling M, Ktz RL, Khanna A, et al. Hepatocytes and
epithelial cells of donor origin in recipients of peripheral blood stem cells.
N Eng J Med2002; 346:738
–6[Abstract/Free Full Text]
- Tran SD, Pillemer SR, Dutra A, et al. Differentiation of
human bone marrow-derived cells into buccal epithelial cells in vivo:
a molecular analytical study. Lancet2003; 361:1084
–8[Medline]
- Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM.
Contribution of transplanted bone marrow cells to Purkinje neurones in human
adult brains. Proc Natl Acad Sci USA2003; 100:2088
–93[Abstract/Free Full Text]
- Caplice NM, Bunch TJ, Stallboerger PG, et al. Smooth
muscle cells in human coronary atherosclerosis can originate from cells
administered at marrow transplantation. Proc Natl Acad Sci
USA 2003;100,4754
–9[Abstract/Free Full Text]
- Deb A, Wang S, Skelding KA, et al. Bone marrow derived
cardiomyocytes are present in adult human heart: a study of gender mismatched
bone marrow transplantation patients. Circulation2003; 107:1247
–9[Abstract/Free Full Text]
- Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B.
Transplanted bone marrow generates new neurons in human brains.
Proc Natl Acad Sci USA2003; 100:1364
–9[Abstract/Free Full Text]
- Kataoka K, Medina RJ, Kageyama T, et al. Participation of
adult mouse bone marrow cells in reconstitution of skin. Am J
Pathol 2003;163:1227
–31[Abstract/Free Full Text]
- Badiavas EV, Abedi M, Butmarc J, Flanga V, Quesenberry P.
Participation of bone marrow derived cells in cutaneous wound healing.
J Cell Physiol2003; 196:245
–50[Medline]
- Stepanovic V, Awad O, Jiao C, Dunnwald M, Schatteman GC. Leprdb
diabetic mouse bone marrow cells inhibit skin wound vascularisation but
promote wound healing. Circulation Res2003; 92:1247
–53[Abstract/Free Full Text]
- Badiavas EV, Falanga V. Treatment of chronic wounds with bone
marrow-derived cells. Arch Dermatol2003; 139:510
–16[Abstract/Free Full Text]
- Orlic D, Kajstura J, Chimenti S, et al. Mobilised bone
marrow cells repair in infarcted heart, improving function and survival.
Proc Natl Acad Sci USA2001; 98:10344
–9[Abstract/Free Full Text]
- Seiler JG, Pohl T, Wustmann K, et al. Promotion of
collateral growth by GM-CSF in patients with coronary artery disease: a
randomised double blind placebo-controlled study.
Circulation2001; 104:2012
–15[Abstract/Free Full Text]
- Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone
marrow stromal cells suppress T-lymphoctye proliferation induced by cellular
or non-specific mitogenic stimuli. Blood2002; 99:3838
–43[Abstract/Free Full Text]
- Shoham T, Parameswaran R, Shav-Tal Y, Brda-Saad M, Zipori D. The
mesenchymal stroma negatively regulates B cell lymphopoiesis through the
expression of Activin A. Ann N Y Acad Sci2003; 996:245
–60[Medline]
- Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal
stem cells suppress lymphocyte proliferation in vitro and prolong
skin graft survival in vivo. Exp Hematol2002; 30:42
–8[Medline]
- Liechty KW, MacKenzie TC, Shaaban AF, et al. Human
mesenchymal stem cells engraft and demonstrate site-specific differentiation
after in utero transplantation in sheep. Nat
Med 2000;6:1282
–6[Medline]
- Devine S, Bartholomew AM, Mahmud N, et al. Mesenchymal
stem cells are capable of homing to the bone marrow of non-human primates
following systemic infusion. Exp Hematol2001; 29:244
–5[Medline]
- Devine S, Cobbs C, Jennings M, Bartholomew A, Hoffman R.
Mesenchymal stem cells distribute to a wide range of tissues following
systemic infusion in non-human primates. Blood2003; 101:2999
–3001[Abstract/Free Full Text]
- Lee ST, Jang JH, Cheong JW, et al. Treatment of high-risk
acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by
co-infusion of T-cell depleted haematopoietic stem cells and culture-expanded
marrow mesenchymal stem cells from a related donor with one fully mismatched
human leucocyte antigen haplotype. Br J Haematol2002; 118:1128
–31[Medline]
- Koc ON, Gerson SL, Cooper BW, et al. Rapid haematopoietic
recovery after co-infusion of autologous blood stem cells and culture-expanded
marrow mesenchymal stem cells in advanced breast cancer patients receiving
high dose chemotherapy. J Clin Oncol2000; 18:307
–16[Abstract/Free Full Text]
- Horwitz EM, Prockop DJ, Gordon PL, et al. Clinical
responses to bone marrow transplantation in children with severe osteogenesis
imperfecta. Blood2001; 97:1227
–31[Abstract/Free Full Text]
- Horwitz EM, Gordon PL, Koo WK, et al. Isolated allogeneic
bone marrow-derived mesenchymal cells engraft and stimulate growth in children
with osteogenesis imperfecta: implications for cell therapy of bone.
Proc Natl Acad Sci USA2002; 99:8932
–7[Abstract/Free Full Text]
- Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W.
Allogeneic mesenchymal stem cell infusion for treatment of metachromatic
leukodystrophy (MLD) and Hurler syndrome. Bone Marrow
Transplant 2002;30:215
–22[Medline]
- Hamano K, Nishida M, Hirata K, et al. Local implantation
of autologous bone marrow cells for therapeutic angiogenesis in patients with
ischaemic heart disease: clinical trial and preliminary results.
Jpn Circulation J2001; 65:845
–7
- Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted
myocardium by autologous intracoronary mononuclear bone marrow cell
transplantation in humans. Circulation2002; 106:1913
–18[Abstract/Free Full Text]
- Assmus B, Schachinger V, Teupe C, et al. Transplantation
of progenitor cells and regeneration enhancement in acute myocardial
infarction (TOPCARE-AMI). Circulation2002; 106:3009
–17[Abstract/Free Full Text]
- Fuchs S, Satler LF, Komowski R, et al. Catheter-based
autologous bone marrow myocardial injection in no-option patients with
advanced coronary artery disease: a feasibility study. J Am Coll
Cardiol 2003;41:1721
–4[Abstract/Free Full Text]
- Perin EC, Dohmann HF, Borojlevic R, et al.
Transendocardial, autologous bone marrow cell transplantation for severe,
chronic ischemic heart failure. Circulation2003; 107:2294
–302[Abstract/Free Full Text]
- Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in
ischaemic myocardium by intramyocardial autologous bone marrow mononuclear
cell implantation. Lancet2003; 361:47
–9[Medline]
- Stamm C, Westphal B, Kleine HD, et al. Autologous bone
marrow stem-cell transplantation for myocardial regeneration.
Lancet2003; 361:45
–6[Medline]
- Galinanes M, Loubani M, Davies J, Chin D, Pasi J, Bell PR.
Autotransplantation of unmanipulated bone marrow into scarred myocardium is
safe and enhances cardiac function in humans. Cell
Transplant 2004;13:7
–13[Medline]
- Wollert KC, Meyer GP, Lotz J, et al. Intracoronary
autologous bone marrow cell transfer after myocardial infarction: the BOOST
randomised controlled clinical trial. Lancet2004; 364:141
–8[Medline]
- Stamm C, Kleine HD, Westphal B, et al. CABG and bone
marrow stem cell transplantation after myocardial infarction. J
Thorac Cardiovasc Surg2004; 52:152
–8
- Hess D, Li L, Martin M, et al. Bone marrow-derived stem
cells initiate pancreatic regeneration. Nat Biotechnol2003; 21:763
–70[Medline]
- Toma JG, Akhavan M, Fernandes KJL, et al. Isolation of
multipotent adult stem cells from the dermis of mammalian skin. Nat
Cell Biol 2001;3:778
–84[Medline]
- Joannides A, Gaughwin P, Schwiening C, et al. Efficient
generation of neural precursors from adult human skin: astrocytes promote
neurogenesis from skin-derived stem cells. Lancet2004; 364:172
–8[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. Hannouche, A. Raould, R.S. Nizard, L. Sedel, and H. Petite
Embedding of Bone Samples in Methylmethacrylate: A Suitable Method for Tracking LacZ Mesenchymal Stem Cells in Skeletal Tissues
J. Histochem. Cytochem.,
March 1, 2007;
55(3):
255 - 262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kochhar
Adult bone-marrow stem cells
J R Soc Med,
December 1, 2004;
97(12):
609 - 610.
[Full Text]
[PDF]
|
|
|
TOP
INTRODUCTION
MESENCHYMAL STEM CELLS
