Stem and progenitor cells in human umbilical cord blood.
ABSTRACT Both stem cells and progenitor cells are present in umbilical cord blood (UCB) at a high frequency, making these cells a major target population for experimental and clinical studies. As the use of autologous or allogeneic hematopoietic stem cell transplantation in the treatment of various diseases has grown rapidly in recent years, the concept of UCB banking for future use has drawn increasing interest. Stem and progenitor cells derived from UCB offer multiple advantages over adult stem cells, such as their immaturity (which may play a significant role in reducing rejection after transplantation into a mismatched host) and ability to produce large quantities of homogeneous tissue or cells. These cells can also differentiate across tissue lineage boundaries into neural, cardiac, epithelial, hepatic, and dermal tissues. Human UCB provides an alternative cell source that is ethically acceptable and widely supported by the public. This paper summarizes the characteristics of human UCB-derived stem and progenitor cells and their potential therapeutic use for tissue and cell regeneration.
Article: Multipotential cells in the bone marrow stroma: regulation in the context of organ physiology.[show abstract] [hide abstract]
ABSTRACT: Multipotential (osteogenic, adipogenic, chondrogenic, and myelosupportive) cells associated with the bone marrow stroma are revealed by in vitro or in vivo differentiation assays. If considered in the context of development, growth, and adaptive changes of bone as an organ, the hierarchical organization, histophysiology, and biological significance of the so-called "stromal system" appear distinct from those predicted from the commonly used analogy with the hematopoietic system, with which the stromal system and its putative "stem" cell are usually compared. The plasticity of differentiated phenotypes and the emergence of individual lineages in a defined temporal succession throughout development and postnatal life reflect the role of the multipotential cells in the stromal system in tissue adaptation and growth, rather than in cell consumption and replacement. This makes the stromal system and its progenitors an interesting paradigm of the biology of an individual cell's flexibility in complex organisms.Critical Reviews in Eukaryotic Gene Expression 02/1999; 9(2):159-73. · 3.08 Impact Factor
Article: Self-renewal, differentiation or death: regulation and manipulation of hematopoietic stem cell fate.[show abstract] [hide abstract]
ABSTRACT: Hematopoietic stem cells (HSCs) are the rare cells from which all hematopoietic cells are derived. The absence of HSCs is not compatible with life because many essential cells, such as myeloid and erythroid cells, are short lived. The hematopoietic system is the first essential organ system that fails following cytotoxic treatments. It is the vulnerability of HSCs that prevents regeneration following treatment and thus long-term survival. Because HSCs have the capacity to regenerate a functional hematopoietic system, the manipulation of these cells in vitro holds many promises for gene-therapeutic and other applications; however, these are severely curtailed by current difficulties in maintaining and expanding HSCs in culture. This review focuses on recent approaches towards understanding how the HSC compartment is regulated in vivo and discusses how this knowledge might be applied to manipulating HSC numbers.Molecular Medicine Today 06/1999; 5(5):201-8.
Article: Cones regenerate from retinal stem cells sequestered in the inner nuclear layer of adult goldfish retina.[show abstract] [hide abstract]
ABSTRACT: To determine whether retinal progenitor cells in the inner nuclear layer give rise to regenerated cones after laser ablation of photoreceptors in adult goldfish retina. Using a technique developed previously in this laboratory, photoreceptors in the retina of adult goldfish were ablated with an argon laser. The mitotic marker, bromodeoxyuridine, was used to label proliferating and regenerated cells, which were identified with cell-specific markers. Cells proliferating locally within lesion included microglia, Müller glia, and retinal progenitors in the inner nuclear layer (INL). The nuclei of both Müller glia and associated retinal progenitors migrated from the inner to the outer nuclear layer. The proliferating retinal progenitors, which express Notch-3 and N-cadherin, regenerated cone photoreceptors and then rod photoreceptors. Previous work has demonstrated that photoreceptors in the goldfish retina regenerate selectively after laser ablation, but the source of regenerated cones has not been identified. The results reported here provide support for the existence of retinal stem cells within the adult fish retina that are capable of regenerating cone photoreceptors. The data also support the involvement of Müller glia in the production of regenerated cones.Investigative Ophthalmology & Visual Science 09/2001; 42(9):2115-24. · 3.60 Impact Factor
Stem and progenitor cells in human umbilical cord blood
Myoung Woo Lee•In Keun Jang•Keon Hee Yoo•
Ki Woong Sung•Hong Hoe Koo
Received: 10 December 2009/Revised: 17 May 2010/Accepted: 25 May 2010/Published online: 25 June 2010
? The Japanese Society of Hematology 2010
in umbilical cord blood (UCB) at a high frequency, making
these cells a major target population for experimental and
clinical studies. As the use of autologous or allogeneic
hematopoietic stem cell transplantation in the treatment of
various diseases has grown rapidly in recent years, the
concept of UCB banking for future use has drawn
increasing interest. Stem and progenitor cells derived from
UCB offer multiple advantages over adult stem cells, such
as their immaturity (which may play a significant role in
reducing rejection after transplantation into a mismatched
host) and ability to produce large quantities of homoge-
neous tissue or cells. These cells can also differentiate
across tissue lineage boundaries into neural, cardiac, epi-
thelial, hepatic, and dermal tissues. Human UCB provides
an alternative cell source that is ethically acceptable and
widely supported by the public. This paper summarizes the
characteristics of human UCB-derived stem and progenitor
cells and their potential therapeutic use for tissue and cell
Both stem cells and progenitor cells are present
Umbilical cord blood ? Stem cells ?
Stem cells (SCs) are capable of self-replication and
differentiation into one or several specific cell types. Two
types of SCs have been identified: embryonic stem cells
(ESCs) in the inner cell mass of the early embryo and adult
(or somatic) tissue-specific stem cells. Adult SCs are
present in the bone marrow (BM) , blood , cornea and
retina , skin , skeletal muscles , dental pulp ,
liver , and brain . As adult SCs can be propagated in
large quantities without losing their ability to differentiate
into different tissue types, they represent a highly valuable
resource for the development of cellular therapies .
Umbilical cord blood (UCB), the blood remaining in the
umbilical cord and placenta after birth, is usually regarded
as medical waste and is routinely discarded. Recently,
however, UCB has been widely used as a rich, ethically
acceptable, source of SCs with high regeneration and dif-
ferentiation potentials. UCB is easily available, can be
routinely harvested without risk to the donor, and is rarely
contaminated with infectious agents such as cytomegalo-
virus (CMV) . UCB has been used as a source of
hematopoietic SCs (HSCs) in various clinical settings since
1988 . Since then, hundreds of thousands of UCB
collections have been frozen and stored throughout the
world in anticipation of their potential use for the treatment
of various disorders. Consequently, investigation into the
potential of cryopreserved UCB as a source of stem cells is
considered vital for future cell-based therapies.
In addition to HSCs, other potential SCs, such as mes-
enchymal SCs (MSCs) [12, 13], unrestricted somatic SCs
(USSCs) , cord blood-derived embryonic-like SCs
(CBEs) , and UCB-derived multipotent progenitor cells
(MPCs)  have been isolated from UCB and charac-
terized according to their morphology, immunophenotypes,
M. W. Lee ? I. K. Jang ? K. H. Yoo ? K. W. Sung ?
H. H. Koo (&)
Department of Pediatrics, Samsung Medical Center,
Sungkyunkwan University School of Medicine, 50 Irwon-dong,
Gangnam-gu, Seoul 135-710, Korea
Int J Hematol (2010) 92:45–51
and proliferation and differentiation potentials. Because
UCB-derived cells are regarded as more primitive than
BM-derived cells, they are a more suitable cell source for
cell-based therapies, regenerative medicine, and tissue
2 Hematopoietic stem cells
Since the first UCB transplantation was performed in 1988
in a child with Fanconi’s anemia , UCB has become a
safe and accepted mode of HSC transplantation (HSCT). In
addition to its low exposure to viruses, UCB transplanta-
tion carries a reduced risk of severe acute graft-versus-host
disease (GvHD), which can occur when one or two human
leukocyte antigen (HLA)-mismatched unrelated donor
transplants are performed. In contrast, BM transplantation
requires strict histocompatibility between donors and
In the cord blood, HSCs are a heterogeneous population
of immature hematopoietic precursor cells that occur rarely
(at a frequency of approximately 1 in 104to 1 in 105cells
postnatally). They are multipotent, and can differentiate
into any one of 10–11 functional hematopoietic lineages.
Consequently, HSCs are capable of repopulating the whole
hematopoietic system within the human lifespan [17, 18].
UCB has a higher primitive HSC content than either BM or
mobilized peripheral blood, and has a higher proliferative
potential with an extended lifespan and longer telomeres
[19, 20]. HSCs contain a small population of CD34?,
primitive, and pluripotent SCs that can self-renew and
generate committed progenitors of both the myeloid and
lymphoid compartments. Although CD34 is not a universal
marker for UCB-derived SCs , it has been used as a
convenient marker for human hematopoietic stem or pro-
genitor cells for autologous and allogeneic transplantation,
resulting in the reconstitution of all hematopoietic lineages
. Most colony-forming cells are found within the
CD34?cell population [23, 24].
While the number of CD34?HSCs in cord blood is
limited, cord blood-derived HSCs obtained following ex
vivo expansion [25, 26] or co-infusion of two or more units
may serve as a reliable source for HSCT. Transplanting ex
vivo-expanded cells reportedly accelerates regeneration.
Ex vivo-expanded cells behave differently from freshly
isolated cells. For example, they result in delayed
engraftment  caused either by a lack of sufficient
progenitors or by the decreased expression levels of hom-
ing and related proteins, along with reduced amplification.
Proteomic surveys of UCB-derived CD34?cells are
designed to investigate how protein expression varies at
different maturation stages within the hematopoietic hier-
archy . More than a dozen proteins have been identified
that are expressed only on CD34?cells. Among these, the
prostatic binding protein (PBP/RKIP) has a predominant
role in proliferation and homing regulatory events [29–31].
This suggests that assessing the cord blood-derived, prim-
itive CD34?cells is important for early engraftment in
HSCT. Although HSCT has been used most often to treat
malignant disease , UCB has been successfully used to
treat nonmalignant diseases such as aplastic anemia and
Fanconi’s anemia . In addition, many investigators
have observed improved engraftment after co-transplanta-
tion of MSCs and cord blood-derived HSCs [34–36].
3 Mesenchymal stem cells
The isolation of MSCs is primarily achieved by plastic
adherence, followed by growth under specific culture
conditions, such as special culture media containing
defined growth factors. To date, the most popular source of
MSCs has been the BM. However, BM aspiration is an
invasive procedure. Moreover, the differentiation potential
of BM-MSCs decreases with age. Recently, MSCs have
been isolated from various sources, including UCB.
Although some investigators failed to isolate MSCs from
UCB-derived cells , other recent attempts have been
successful [12, 13, 38, 39]. MSCs are capable of differ-
entiating into osteoblasts, chondrocytes, adipocytes, and
myogenic and neuronal cells.
We, as well as others [38, 39], have provided strong
evidence for the presence of circulating non-HSCs,
including MSCs, in human UCB. These UCB-MSCs were
strongly positive for MSC-specific cell surface markers
such as CD105 (SH2), CD73 (SH3, SH4), and CD166
(ALCAM), but negative for CD14 (monocyte antigen),
CD31 (endothelial cell antigen), CD34 (HSC antigen),
CD45 (leukocyte common antigen), and CD86 (a co-
stimulatory molecule). The cell surface antigen profile of
UCB-MSCs was essentially the same as that for BM-MSCs
[40, 41]. The UCB-MSCs were more proliferative than
BM-MSCs during early passages, while the total cell
number of expanded UCB-MSCs in long-term cultures was
lower than that of BM-MSCs . These phenomena can
be explained by both intrinsic and/or extrinsic factors. UCB
reportedly contains more primitive SCs than BM, which
may explain why UCB-MSCs are more proliferative than
BM-MSCs during early growth stages. The difference in
the total cell number after long-term culture may be related
to other inherent characteristics of the UCB and BM
samples, including the frequency of MSCs within the cell
The frequency of MSCs in cryopreserved UCB units has
not been clearly defined. Previous studies using colony-
forming unit fibroblast (CFU-F) culture as a surrogate
46M. W. Lee et al.
assay reported that the frequency of BM-MSCs in adults
was one in 3.4 9 104cells. However, fresh UCB and
peripheral blood SCs (PBSCs) did not produce CFU-F at
all [37, 43]. It is possible that MSCs in cryopreserved
UCBs are present at a very low frequency relative to MSCs
in BM. Since a few UCB-MSCs were more proliferative
than BM-MSCs during early passages, the doubling
potential of UCB-MSCs may decrease more quickly than
that of BM-MSCs after a finite number of doublings.
Extrinsic factors affecting growth rate may include differ-
ences in the culture conditions required for UCB-MSCs
and BM-MSCs cultivation (e.g., medium composition,
serum, pH, positive or negative selection, and the effi-
ciency of trypsinization), and the ‘human factor’ that
determines when and how the cultures are passaged. The
precise reason for the differences in growth rate between
BM-MSCs and UCB-MSCs requires further study.
Clinically, the immunomodulatory properties of MSCs
can be used to enhance engraftment and to reduce the
incidence of GvHD after allogeneic HSCT [34–36]. We
previously demonstrated that UCB-MSCs were capable of
suppressing mitogen-induced T cell proliferation to levels
similar to those seen with BM-MSCs . The use of
UCB-MSCs has a major advantage in that it does not
require invasive procedures that could be harmful to the
donor. UCB may be a better third-party source of MSCs
that can be used universally across the HLA barrier. Sev-
eral studies have shown that MSCs possess an intrinsic
homing ability, migrating to the injured tissues and actively
participating in tissue repair. MSCs can repair injured tis-
sue by differentiating into damaged cell types, secreting
appropriate cytokines and growth factors, and undergoing
cell fusion [45–47]. In addition, MSCs possess the unique
ability to suppress immune responses, both in vitro [48, 49]
and in vivo [50–52].
potentials are present in UCB. The in vitro isolation,
expansion, and characterization of UCB-MSCs will be
useful for basic research, and are expected to facilitate the
development of therapeutic strategies, such as cellular and
4 Unrestricted somatic stem cells
Ko ¨gler et al.  identified a rare population of CD45?/
HLA class II-negative SC candidates in UCB, which they
termed unrestricted somatic SCs (USSCs). This cell popu-
lation displayed a robust in vitro proliferative capacity
without spontaneous differentiation, but with intrinsic and
controllable differentiation into cell types found in meso-
dermal, endodermal, and ectodermal lineages . In con-
trast to BM-MSCs , USSCs have a wider differentiation
potential and different immunophenotypes  and mRNA
USSC cultures were initiated from 573 UCB samples
with a total generation frequency of 35.4% (n = 203) .
After 6–20 days, between one and 11 USSC colonies/UCB
were detected, which grew into monolayers within
2–3 weeks. No correlation was observed between suc-
cessful initiation of USSC cultures and the gestational age
([36 weeks), cord blood volume (always[40 mL), num-
ber of nucleated cells in the UCB collections ([2 9 108),
hours elapsed after UCB collection (up to 57 h), or the
number of mononuclear cells (MNCs) in the UCB after
gradient separation . USSCs can be cultured for [20
passages (equivalent to[40 population doublings) without
spontaneous differentiation. USSCs have longer telomeres
than BM-MSCs, which may explain their high expansion
capacity. They also constitute an easily accessible cell
source that has high proliferation capacity without loss of
the normal karyotype during cultivation [14, 55].
USSCs are adherent, spindle-shaped cells of 20–25 lm
in size. They are negative for CD14, CD33, CD34, CD45,
CD49b, CD49c, CD49d, CD49f, CD50, CD62E, CD62L,
CD62P, CD106, CD117, glycophorin-A, and HLA-DR.
They express high levels of CD13, CD29, CD44, CD49e,
CD90, CD105, vimentin, and cytokeratin 8 and 18 and low
levels of CD10 and FLK1 (KDR) . USSCs express
various transcripts for cytokine receptors, transcription
factors, and cell surface markers, including epidermal
growth factor receptor, platelet-derived growth factor
receptor, insulin-like growth factor receptor, runt-related
transcription factor (Runx1), YB1, CD49e, and CD105.
The cells are negative for the chondrogenic extracellular
protein chondroadherin, the bone-specific markers colla-
genase X and bone sialoprotein, the liver- and pancreas-
specific markers Cyp1A1 and PDX-1, and neural markers
such as neurofilament, synaptophysin, tyrosine hydroxy-
lase, and glial fibrillary acid protein .
USSCs are capable of differentiating into various lin-
eages in vitro and in vivo, including neuronal cells, oste-
oblasts, chondrocytes, adipocytes, hematopoietic cells,
cardiomyocytes, purkinje fibers, and hepatic cells .
Transplantation of USSCs reportedly improves left ven-
tricle (LV) function and prevents scar formation and LV
dilation after acute myocardial infarction. Since differen-
tiation, apoptosis, and macrophage mobilization at the
infarct site were excluded as underlying mechanisms,
paracrine effects most likely account for the observed
effect of USSC treatment . In addition, USSCs show
increased secretion of vascular endothelial growth factor
(VEGF) during osteogenic differentiation, as well as
expression of key markers of angiogenesis such as VEGF
receptor-2 and platelet/endothelial cell adhesion molecules.
When transplanted into a bone defect, USSCs might
Stem and progenitor cells in UCB47
support the repair process by pure remineralization and
installation of an angiogenic environment .
USSCs provide an unlimited source of cellular grafts for
therapeutic purposes and exhibit considerable advantages
over other cell types. Autologous cells isolated after birth
can be stored for individual later use. Further investigations
are necessary to analyze the impact of graft-related
immune responses and to compare the outcome of xeno-
geneic and allogeneic USSC transplantation.
5 Cord blood-derived embryonic-like stem cells
McGuckin et al.  reported the reproducible production
of untransformed adherent human SC populations with an
ESC phenotype from UCB, termed cord blood-derived
embryonic-like SCs (CBEs) [15, 58]. The CBEs formed
embryoid body-like colonies that were immunoreactive for
primitive human ESC-specific genes , suggesting that
CBEs were capable of differentiating into neuronal, hepa-
tic, pancreatic, bone, fat, skeletal muscle, and blood vessel
One week after the initial plating of the primary culture,
the adherent cell clusters formed embryoid body-like col-
onies that progressively increased in both size and number.
The adherent colonies could be dissociated at week 6 or 7
and reseeded in second-generation liquid cultures. Second-
generation CBEs formed embryoid body-like structures
with a morphology similar to that of their first-generation
progenitor colonies. The CBEs were grown for up to 6
additional weeks and demonstrated an exponential cell
proliferation pattern. Second-generation CBE populations
significantly expanded (168-fold) from their baseline con-
centration (105cells/mL) to yield 1.68 9 107± 8.84 9
CBEs are negative for the hematopoietic lineage mark-
ers CD45, glycophorin-A, CD38, CD7, CD33, CD56,
CD16, CD3, and CD2, and are positive for CD34, CD133,
and CD164. The CBE colonies are positive for the
embryonic stage-specific antigens SSEA-3 and SSEA-4,
but are negative for embryonic antigen-1 (SSEA-1), con-
firming their undifferentiated phenotype . They also
express the ESC transcription factor Oct-4 involved in
differentiation inhibition and ESC self-renewal . CBE
colonies express the embryonic extracellular matrix com-
ponents Tra 1-60 and Tra 1-81 [15, 58], which most likely
contribute to the colony-like nature of their clustered
Multi-lineage progenitor cells (MLPCsTM, an improved
cell line commercially available from BioE in Minnesota,
USA) are capable of differentiating into bone, fat, skeletal
muscle, blood vessels, and liver/pancreatic cells .
Neural precursor and cells generated from CBEs may be
used for in vitro drug testing and cell-based assays, and
potentially for clinical transplantation.
6 Multipotent progenitor cells
While studying whether other SCs are present in either
fresh or cryopreserved UCB, our group isolated a novel cell
line from an SC population in human UCB . Seeded
UCB-derived MNCs formed adherent colonies under
optimized culture conditions. Over a 3- to 4-week culture
period, the colonies gradually developed into adherent
monolayers that exhibited a homogeneous fibroblast-like
morphology and immunophenotype, and were highly pro-
liferative. We refer to these cells as UCB-derived multi-
potent progenitor cells (MPCs) .
MPCs were obtained from 95.5% of UCB harvests,
without the need for complicated separation procedures.
The cells were negative for CD34, CD49a, CD62E, CD73,
CD90, CD104, and CD133, and expressed high levels of
CD14, CD31, CD44, CD45, and CD54, with variable
expression of CD105 and CD166. The surface antigen
profile of MPCs was sustained for more than 12 weeks, and
MPCs were highly proliferative with a 28-fold increase in
cell number at 12 weeks. While the MPCs were negative for
CD34 and CD133 at late culture times, these HSC-specific
surface markers were fully expressed in the adherent, col-
onized cells at early culture times. The morphology of the
colonized cells closely resembled that of cells in HSC
colonies . Thus, isolated MPCs can be derived from
HSCs or their precursors in UCB. However, the relationship
between MPCs and HSCs in UCB requires further investi-
gation. The MPCs were negative or only weakly positive for
MSC-related markers such as CD73 (SH3, SH4), CD105
(SH2), and CD166 (ALCAM). They had a rod-like shape
and were relatively small and plump compared with MSCs.
Immunophenotypic and morphological data indicated that
the MPCs were distinct from stromal MSCs. In addition,
CD45 was expressed in MPCs, but not in human USSCs or
CBEs. Thus, MPCs are characteristically different from
HSCs, MSCs, USSCs, and CBEs (Table 1).
Isolated MPCs were capable of differentiating into three
germinal tissue-specific cell types, osteoblasts, myoblasts,
endothelial cells, hepatocytes , and neuronal cells .
In a preclinical study, MPCs promoted functional recovery
in rats with spinal cord injury . In addition, trans-
planted MPCs successfully incorporated into the liver in rat
models with hepatic injury, and differentiated into
functional hepatocytes that expressed CK-18 and albumin,
a hepatocyte-specific marker . Thus, MPCs could
potentially serve as a universal allogeneic stem/progenitor
cell source for use in the development of SC-based
48 M. W. Lee et al.
The use of SCs for cell replacement therapy constitutes a
promising approach for the treatment of various diseases
and injuries. Ideally, such cells should exhibit two key
properties: (1) a high level of proliferation in vitro,
allowing production of a large number of cells from a
limited amount of donor material, and (2) phenotypic
plasticity, facilitating differentiation into various tissue-
specific cells. To date, several approaches to SC therapies
have been used to treat various diseases. However, many
studies using SCs present serious ethical problems related
to the destruction of the human embryo and possible
teratoma formation in the recipient. Thus, SCs from
non-embryonic sources offer a real prospect for clinical
intervention in the short term and have been successful for
the treatment of over 70 diseases and disorders.
Initially, UCB and BM SCs were used as an intervention
in only blood- or immune system-related problems. How-
ever, their use in the treatment of genetic diseases and their
application to regenerative medicine has opened new pos-
sibilities that were previously reserved for only ESCs.
Progress in SC therapy has been impeded by the need to
develop clinical-grade protocols for both the harvesting
and processing of the SC source into a transplantation-
suitable form. Determination of the stage at which a SC
source should be for transplantation, whether as a primary
SC or expanded and/or developed progenitor population
and/or fully developed mature cell, is a limiting factor that
still requires meticulous research.
In conclusion, various stem and progenitor cells with
different characteristics that can be derived from fresh or
cryopreserved UCB could be good candidates for use in SC
therapy. Other SCs may exist within UCB that are even
more primitive and have a higher potential for plasticity.
Further studies are warranted to identify the yet unrecog-
nized value of UCB-derived SCs.
National R&D Program for Cancer Control, Ministry for Health,
Welfare and Family affairs, Republic of Korea (Project no: 0720230).
This study was supported by a grant from the
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cells derived from umbilical cord blood
Immunophenotypic comparison of stem and progenitor
Cell surface markerHSCMSC USSCCBEMPC
Values of immunophenotyping were determined by flow cytometry
on a FACScan (BD Sciences)
HSC hematopoietic stem cell, MSC mesenchymal stem cell, USSC
unrestricted somatic stem cell, CBE cord blood-derived embryonic-
like stem cell, MPC multipotent progenitor cell, CD34 and CD133
hematopoietic stem cell, CD14 monocyte, CD45 leukocyte common,
CD44 hyaluronan receptor, CD73 (SH3, SH4) mesenchymal stem
cell, CD90 (Thy-1) Thy-1 membrane glycoprotein precursor, CD105
(SH2) mesenchymal stem cell, CD166 ALCAM (activated leukocyte
cell adhesion molecule), ? strong positive, - strong negative
Stem and progenitor cells in UCB 49