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Research has demonstrated that it
is possible to unlocked the
differentiated state and allow mature
cells to return to immature state from
each all cells can be derived.
Stem Cells – general characteristic and sources
Monika Bieniasz1, Andrzej Chmura1, Artur Kwiatkowski1
Attribution: Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
1. Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
#Corresponding author: Monika Bieniasz MD, PhD, Department of General and Transplantation Surgery, Warsaw Medical University,
Nowogrodzka 59 street, 02-006 Warsaw, Poland. Phone:+48 225021470, Fax:+48 225022155, e-mail: [email protected]
Stem Cells
stem cells, induced pluripotent stem cells, somatic nuclear transfer, reprogramming, regenerative medicine
3 104
no conflicts of interest
Stem cells are self-renewal and can generate differentiated progeny cells. There is an explosion of interest in
stem cells over the last few years. It is related to the scientific findings concerning cellular reprogramming.
Two scientists, John B. Gurdon and Shinya Yamanaka, have discovered that mature, specialised cells can be
reprogrammed to become immature cells. This scientific findings revolutionised our understanding of how cells
and organisms developed and provides hope for the use of stem cells in the regenerative medicine and treatment for the diseases. It is hope for patients suffering from incurable diseases in which conventional treatment
does not give satisfactory results. It is great expectations for regenerative medicine concerning cell-based therapy such diseases as: diabetes, myocardial infarction, stroke, spinal cord injury, neurodegenerative disease of
the brain, liver and kidney damage. The objective of this article are presentation of general characteristic and
sources of stem cells.
here is considerably increase of interest in stem
cells over the last few years. It is related to the
scientific findings concerning cellular reprogramming which revolutionised our understanding
of how cells and organisms develop. Two scientists
have discovered that mature, specialised cells can
be reprogrammed to become immature cells capa-
ble of developing into all tissues of the body. John
Bertrand Gurdon discovered in 1962 that the specialisation of cells is reversible. In a classic experiment,
he removed the nucleus of a fertilized egg cell from
a frog and replaced it with the nucleus of a mature
cell taken from a mature intestinal cell. This modified
egg cell developed into a normal tadpole. The DNA
MEDtube Science Jun, 2014; Vol.II (2)
of the mature cell still had all the information needed
to develop all cells in the frog. More than 40 years
later, in 2006, Shinya Yamanaka discovered, how
intact mature cells in mice could be reprogrammed
to become immature stem cells. He could reprogram
mature cells to become pluripotent stem cells by
introducing only a four genes, which are currently
known as a “Yamanaka’s quartet”. In 2012 Sir John
B. Gurdon and Shinya Yamanaka (fig. 1) were jointly
awarded The Nobel Prize in Physiology or Medicine
„for the discovery that mature cells can be reprogrammed to become pluripotent” (video 1) [1]. In the
long-term, these discoveries may lead to new medical treatments.
Progress in stem cell research provides hope for the
use of stem cells in the regenerative medicine and
treatment for the diseases. Special expectations concerning attempts to harness stem cells are associated with the treatment of such diseases, as diabetes,
myocardial infarction, muscular dystrophy, stroke,
spinal cord injury, neurodegenerative disorders and
inflammatory bowel diseases. A potential use of stem
cells for medical treatment was illustrated on the
figure 2 [2].
Stem cells (SCs) have several characteristics that
make them unique in comparison with other mammalian cells. Stem cells definition includes three main
criteria [3, 4]:
1. ability to self-renew, for several cell divisions,
which is a prerequisite for sustaining the stem
cell pool,
2. ability to generate at the single cell level differentiated progeny cells, in general of multiple
3. ability to functionally reconstitute a given tissue
in vivo.
Stem cells reveal high plasticity [5]. The plasticity can
be explain by transdifferentiation (direct or indirect)
and fusion. Transdifferentiation is describes by the
conversion of a cell of one tissue lineage into a cell
of an entirely distinct lineage with loss of the tissue-specific markers and function of the original cell
type, and acquisition of the identity of a different phenotype through the expression of the gene pattern of
other tissue (direct) or through the achievement of a
more primitive less specialized state and the successive differentiation to another cell type (indirect or
dedifferentiation) [6].
Stem cells can be classified under four categories
that describe their potency, or, the extent into which
they can differentiate. These four categories are totipotent, pluripotent, multipotent and monopotent. The
developmental hierarchy of stem cells was presented
in table 1 [7] and fig. 4 [8].
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Most primitive stem cell of the adult mammalian is
the zygote, which is the result of the fusion of two
haploid cells during fertilization. The zygote, as a
totipotent stem cell, is able to give rise to both the
embryo and the placenta. The “artificial” counterpart
of the totipotent zygote is referred to as a clonote.
The clonote can be created in the laboratory with an
experimental approach known as somatic cell nuclear transfer, involving removal of the nucleus from
a somatic cell and its transfer into an enucleated
oocyte. On the second day after fertilization (24 to
25 hours), the zygote has undergone the first cleavage to produce a 2-cell embryo. The first blastomers
obtained from the first division of the zygote or the
clonote are still totipotent stem cells [9]. Approximately four days after fertilization, when the blastomers
have divided into 32-cell stage, the embryo is called
a morula. Cells which form the morula have already
lost their totipotency and become pluripotent. The
growing morula develops a central cavity and becomes the blastocyst, which contains cells that are
precursors for extra-embryonic tissues. This distinct
group of cells is known as the inner cell mass (ICM)
(fig. 3). Pluripotent stem cells are isolated from ICM
of a blastocyst, from the epiblast of cylinder-stage
embryo (EPSC) or could be derived in ex vivo cultures from epiblast-derived primordial germ cells (PGC)
– as a population of so-called embryonic germ cells
(EGC). Pluripotent stem cells give rise to all three
germ layers (ectoderm, mesoderm and endoderm),
but not to the trophoblast (fig. 4) [8]. Embryonic development and the subsequent adult life are viewed as
a continuum of decreasing differentiation ability. After
implantation and gastrulation, cells become progressively restricted to specific lineages. Multipotent stem
cells contribute to monopotent stem cells that are
committed to particular organ/tissues.
In recent years, there were discovered a small
population of stem cells, which has been named
very small embryonic-like stem cells (VSELs). Polish
scientist, professor Mariusz Z. Ratajczak, and his
scientific team hypothesize that VSELs could be a
population of epiblast-derived pluripotent stem cells,
which is deposited in various tissues (e. g., bone
marrow) and survives into adulthood [8].
Stem cells can be also classified into four types based on their origin. These four categories contain [5]:
stem cells from embryons,
stem cells from fetus,
stem cells from the umbilical cord,
stem cells from the adult.
Human embryonic stem cells (hESCs) are obtained
from the inner cell mass of the 5- to 6-day old human
blastocyst. During embryonic development, the ICM
develops into two distinct layers, the epiblast and the
hypoblast. The hypoblast forms the yolk sac, and the
epiblast differentiates into three primordial germ layers (ectoderm, mesoderm and endoderm). Embryonic
stem cells present two distinctive properties: they are
able to differentiate into all derivatives of three primary germ layers (pluripotency), and they are capable
of propagating themselves indefinitely, under defined
conditions [10]. The main problem concerning embryonic stem cells application is the risk of teratoma
and other cancer formation. The understanding the
mechanisms of embryonic stem cells differentiation
should provide answers for reprogramming of stem
cells from adult tissues [7].
Human embryonic germ cells (hEGCs) originate from
the primordial germ cells of the gonadal ridge of 5- to
9-week old fetuses and are pluripotent. Human embryonic germ cells have been successfully isolated
and characterised [11].
largely in the bone marrow, where hematopoietic
stem cells reside, divide and differentiate into all the
blood cell types.
Bone marrow possesses stem cells that are hematopoietic stem cells and mesenchymal in origin [10].
Hematopoietic stem cells (HSCs) are present in circulating blood and umbilical cord blood and are able to
sustain production of all blood cells throughout life.
Bone marrow transplantation and peripheral blood
stem cell transplantation are current clinical procedures to restore stem cells that have been destroyed by
high doses of chemotherapy and/or radiation therapy
Mesenchymal stem cells (bone marrow stroma)
Fetal stem cells are primitive cell types found in the
organs of fetuses. These stem cells are capable to
differentiate into two types of stem cells: pluripotent
stem cells and hematopoietic stem cells. Fetal blood,
placenta and umbilical cord are rich sources of fetal
hematopoietic stem cells [10, 12]. The tissue rejection
due to fetal cells application may limit the usefulness
of fetal stem cells [12].
Umbilical cord stem cells contais circulating stem
cells. The cellular contents of umbilical cord blood
appear to be quite distinct from those of bone marrows and adult peripheral blood [13]. The frequency
of umbilical cord blood hematopoietic stem cells
equals or exceeds that of bone marrow and they are
known to produce large colonies in vitro, have long
telomeres and can be expanded in long term culture
Adult stem cells are any stem cells obtained from
mature tissues. Most adult stem cells are lineage-restricted (multipotent) and are predominantly referred to by their tissue origin (endothelial stem cells,
mesenchymal stem cells, adipose-derived stem cells,
etc.) [14]. They play essential roles on local tissue repair and regeneration. The therapeutic application of
adult stem cells is not as controversial as embryonic
stem cells, because the production of adult stem
cells does not require the destruction of embryo [12].
Adult stem cells include:
hematopoietic stem cells,
mesenchymal stem cells,
hepatic stem cells,
pancreatic stem cells,
intestinal stem cells,
epidermal stem cells,
bone and cartilage stem cells,
neural stem cells,
eye stem cells.
Hematopoietic stem cells (bone marrow and
peripheral blood)
Blood cells and certain kinds of epithelial cells survive for the shortest time in comparison to all the cell
types in the body. The replenishment process occurs
Mesenchymal stem cells (MSCs) are multipotent
stem cells and can be isolated from several other
tissues, including adipose tissue, placenta, amniotic
fluid, umbilical cord blood and fetal tissues. MSCs
are able to differentiate into adipocytes, osteocytes,
chondrocytes, smooth muscle cells and hematopoietic supportive stroma [15]. In a steady state and or
in response to injury, turnover of stromal tissue and
occurs through the participation of a population of
stem cells found in the stromal tissue [16].
The isolation of a large number of potent HSCs/
MSCs sets the basis of new methods for tissue regeneration and cell therapy [17].
Hepatic stem cells
Mammals are said to survive surgical resection of at
least 75% of the liver by regeneration. The original
tissue can be restored in 2-3 weeks [18]. Liver mass
is restored primarily through the activation of hepatocytes [19]. It is suggested that mature hepatocytes
could serve their own physiologic precursors [20].
Liver oval cell, a blast-like cell and with the capability
of self renewing and multipotent differentiation, is
considered as the liver-specific stem cell. In multiple
independent studies, these liver oval cells have been
shown to present molecular markers of adult hepatocytes, (albumin, cytokeratins 8 and 18), bile duct cells
(cytokeratins 7 and 19, OV-6, A6), fetal hepatoblasts
(AFP), and haematopoietic stem cells (Thy -1, Sca-1,
c-kit). Oval cells isolated from the liver represent a
promising source for cell-based therapy [12].
Pancreatic stem cells
Pancreatic stem cells have the potential to differentiate into all three germ layers. The best candidate
sources for adult pancreatic stem or progenitor cells
are: duct cells, exocrine tissue, nestin-positive islet
-derived progenitor cells, neurogenin-3-positive cells,
pancreas-derived multi-potent precursors; and mature beta-cells. Major markers present on the surface
of pancreatic stem cells include Oct-4, Nestin, and
c-kit. DCAMKL-1 is a novel putative stem/progenitor
MEDtube Science Jun, 2014; Vol.II (2)
marker, can be used to isolate normal pancreatic
stem/progenitors, and potentially regenerate pancreatic tissues [12].
Intestinal stem cells
either due to injury or diseases, it is unable for the
corneal ocular repairing and regeneration [32]. It is
suggested that many corneal disorders such as in keratoconus, anirdia and alkali burns are likely associated with the corneal stem cell deficiency [12].
The gastrointestinal epithelial lining undergoes rapid
renewal throughout life. Epithelial cell renewal in the
intestine is sustained by multipotent stem cells located in the crypts of Lieberhahn. In the small intestine,
epithelial cells of enterocytic, goblet and enteroendocrine origin differentiate as they migrate from a
crypt up an adjacent villus and leave the intestine
ones they reach the villus tip. In the colon, epithelial
cells migrate from the crypt toaflat surface cuff that
surround its opening [21].
Epidermal stem cells
Pluripotent stem cells obtained from banked
embryons derived by fertilization
The human skin comprises the outer epidermis and
underlying dermis. Keratinocyte is the most important
cell type in the epidermis. Keratinocyte divides and
is housed in the basal layer of the epidermis. The
epidermis houses stem cells at the base of the hair
follicle and their self-renewing properties allow for the
re-growth of hair and skin that occurs continuously.
New keratinocytes are produced continuously during
adult life to replace squames shed from the outer
skin layers and the hairs that are lost. Stem cells
differentiate into an intermediate cell called “the
transient amplifying cell” [22]. “The transient amplifying cell” can regenerate themselves and also give
rise to the more differentiated keratinocytes that are
displaced from the basement membrane and form
the superficial layers of the epidermis [23].
Bone and cartilage stem cells
Bone itself has been found to have both uncommitted stem cells as well as committed osteoprogenitor
cells [24, 25]. Articular cartilage has a very limited
capacity of repair in vivo. In case of injury to cartilage, stem cells do participate in the repair process
[26, 27].
Neural stem cells
Neural stem cells are known to reside in the subventricular zone of the forebrain and in the dental gyrus
of the hippocampus and they consistently generate
new neurons [28-30].
Eye stem cells
Human corneal stem cells locate on cornea limbus,
which is between the colored and white part of the
eye. In steady state and in the response to injury to
the corneal epithelium, the limbal corneal stem cells
divide to produce daughter transient amplifying cells
that proliferate, migrate onto the central cornea and
become terminally differentiated to replace the lost
cells [31]. In the case of limbal stem cell deficiency,
MEDtube Science Jun, 2014; Vol.II (2)
The first documentation of the isolation of embryonic
stem cells from human blastocysts was in 1994 [10].
Since then, obtain and culture techniques of human
embryonic stem cells have been substantially improved. Pluripotent stem cells can be potentially derived
from four sources, as shown in table 2 and video 2
[7]. Each of these potential sources has advantageous and limitations [7].
The method of obtaining pluripotent stem cells from
banked embryons, derived by fertilization for clinical
purposes, was abandoned because of the fact that
banked embryos cells has incompatibility with the
potential recipient cells, and therefore embryonic cell
lines will differentiate into cells with another histocompatibility antigens than the potential recipient [7].
Addictionally, use of human embryos faces ethical
controversies that hinder the applications of human
ES cells. It is difficult to generate patient- or disease
-specific ES cells, which are required for their effective application [33].
Pluripotent SCs isolated from embryons derived
by therapeutic cloning
The method of therapeutic cloning involves in vitro creating an cell, which in terms of development
potential is equivalent to the zygote [34]. This cell is
called „a clonote”. Oocyte cytoplasm, from which
the nucleus containing the haploid number of chromosomes is removed, and then the mature cell
nucleus containing diploid number of chromosomes
is inserted in it, is used to create a clonote. The
chromosomes inserted into the oocyte cytoplasm are
„de-differentiated”. Oocyte cytoplasm is „biochemical
incubator,” which includes a lot of enzymes that can
modify the DNA. DNA is undergone demethylation
and rearrangement reaction. It is determined the
appropriate pattern of methylation and acetylation of
histone proteins, which leads to remodel of chromatin
structure and allows to return differentiated DNA, obtained from the donor’s somatic cell, to the state as it
appeared in the fertilized oocyte. It creates the possibility of early developmental gene expression. This
procedure is called somatic cell nuclear transfer. The
created clonote has genes which are compatibile with
the genes from a cell which was a nuclear donor. The
resulting embryonic stem cells are perfectly matched
to the patient’s immune system and no immunosupressants would be require to prevent rejection [35].
The main obstacle to extensive use of therapeutic
cloning is limited access to human oocytes, and the
observations that the pluripotent stem cells derived
from animal clonote, similar to embryonic cells, can
form teratomas in experimental animal study [7].
Pluripotent SCs isolated from adult tissues
Adult stem cells are, especially in the area of hematopoietic stem cells, better understood than any other
aspect of stem cell biology [36]. Cell-based therapy dates back to the first bone marrow transplant
in 1956 [37]. It has been found that progenitor cell
populations are present in many tissues other than
the bone marrow, including the gastrointestinal tract,
skin, brain and muscle [35].
Adult stem cells tend to be tissue-specific and can
differentiate into cell types associated with the organ
system in which they reside [38, 39]. Currently, it is
known that niches of stem cells exist in many tissues,
such as bone marrow, blood, liver, pancreas, brain, skin, the gastrointestinal tract, the eye, skeletal
muscle, and dental pulp [35].
Induced pluripotent stem cells (iPSCs)
Induced pluripotent stem cells (iPSCs) are obtained
by in vitro transformation of cultured adult somatic cells with genes encoding transcription factors
crucial for the development of embryonic stem cells
(Oct-4, Klf4, Nanog, c-myc) [7].
In mid 2006, Takayashi i Yamanaka reported that
mouse embryonic fibroblasts and adult mouse
fibroblast can be reprogrammed into an induced
pluripotent state [Takahashi, Zhao]. They evaluated
24 genes that were thought to be important for embryonic stem cells and identified 4 crucial genes that
were required to bestow embryonic stem cell-like
properties on fibroblasts. Mouse embryonic fibroblasts and adult fibroblasts were co-transuced with
retroviral vectors, each carrying Oct3/4, Sox2, c-Myc
and KLF4. The resultant iPSCs possessed the immortal growth characteristics of self-renewing ESCs.
iPSCs were injected into mouse blastocyst and they
contributed to a variety of diverse cell types, demonstrating their developmental potential [40].
mice [Zhao].
On the threshold of the third millennium, the man reached for the technology, which has been attributed
to Supreme Beings. Progress in biological sciences
and genetics drew secrets of organisms formation
and their regeneration. The Nobel Prize winners, Sir
John Gurdon and Shinya Yamanaka, introduce us in
the exciting world of stem cells and regenerative medicine. Progress in stem cells research provides hope
for the use of stem cells in the regenerative medicine.
It can be assumed that stem cells will be used for
any treatment options, including extending the life, in
the near future. It has been suggested that instead of
whole organ transplantation, surgeons will transplant
cells with high regenerative potential, which will repair
damaged organs. Continuous technical progress give
the scientists hope for the immediate future and for
the realization of the mythological idea of regeneration, which was describe in the story of Prometheus.
MEDtube Science Jun. 2014; 2(2), 8-14.
Fig. 1. Sir John Bertrand Gurdon (left) and Shinya Yamanka (right) during the Nobel Prize Award Ceremony [1].
Fig. 2. Potential uses of stem cells [2].
Fig. 3. Blastocyst opened to reveal the inner cell mass.
Fig. 4. Developmental hierarchy in stem cell (SC) compartment [8].
Reprogramming by transduction of 4 defined factors can be done with human cells [41]. Yamanaka’s
group determined that the introduction of a mouse
receptor for retroviruses into human dermal fibroblasts using a lentivirus improved the transduction
efficiency from 20% to 60%. Yamanaka demostrated that retrovirus-mediated transfection of Oct3/4,
Sox2, c-Myc and Klf4 generates human iPSCs that
are similar to human embryonic stem cells in terms of
morphology, proliferation, gene expression, surface
markers and teratoma formation. iPSCs can differentiate into all three germ layers in vitro and form
teratomas when are injected into immunodeficient
MEDtube Science Jun, 2014; Vol.II (2)
Table 1. Developmental hierarchy in stem cell (SC) compartment [7].
Table 2. Potential sources of stem cells [7].
FIG. 3.
Give rise to both embryo and placenta. The physiological totipotent stem cell is a zygote or first cleavage blastomeres. The
artificial counterpart is a clonote obtained by nuclear transfer
to an enucleated oocyte.
Give rise to all three germ layers of the embryo after injection
to the developing blastocyst. Pluripotent stem cells from the
inner mass (ICM) of the blastocyst are known as embryonic
stem cells (ESCs).
Give rise to cells from one or two of the germ cells layers
(ecto--, meso- or endoderm) only.
Tissue-committed stem cells that give rise to cells of one
lineage, e. g. hematopoietic stem cells, epidermal stem cells,
neural stem cells, liver stem cells, intestinal epithelium stem
cells or skeletal muscle stem cells.
McHugh PR. Zygote and “Clonote” – The Ethical Use of Embryonic Stem Cells. NEJM 2004; 351 (3): 209-211 [43].
SCs isolated
from banked
derived by
SCs isolated
derived by
SCs isolated
from adult
SCs obtained
in result to
somatic cell
transformation (induced
stem cells iPSCs)
Risk of
HLA incompatibility
Donor of
oocyte is
* The problem differently perceived by the major world religions.
Video 1. The Nobel Prize Ceremony 2012.
Video 2. The sources of stem cells.
PGC – epiblast-derived primordial germ cells
MEDtube Science Jun, 2014; Vol.II (2)
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