Tissue and Cell 65 (2020) 101351

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Tissue and Cell

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Umbilical cord stem cells: Background, processing and applications T

a a a b
Shumukh M. Alatyyat , Houton M. Alasmari , Omamah A. Aleid , Mohamed S. Abdel-maksoud ,
Nehal Elsherbinyc,d,*
a
Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
b
Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
c
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
d
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

A R T I C LE I N FO A B S T R A C T

Keywords: Stem cells have currently gained attention in the field of medicine not only due to their ability to repair dys-
Umbilical cord stem cells functional or damaged cells, but also they could be used as drug delivery system after being engineered to do so.
Processing Human umbilical cord is attractive source for autologous and allogenic stem cells that are currently amenable to
Applications treatment of various diseases. Human umbilical cord stem cells are -in contrast to embryonic and fetal stem cells-
ethically noncontroversial, inexpensive and readily available source of cells. Umbilical cord, umbilical cord vein,
amnion/placenta and Wharton’s jelly are all rich of many types of multipotent stem cell populations capable of
forming many different cell types. This review will focus on umbilical cord stem cells processing and current
application in medicine.

1. Introduction Multipotent stem cells such as mesenchymal stem cells. In this class,
cells can differentiate into a discrete range of cell types. Hence,
Stem cells are currently believed as the next future in medicine, due multipotent stem cells possess a narrower spectrum of differentia-
to their considerable therapeutic and biotechnological benefits in tion compared to PSCs. d) Oligopotent stem cells such as myeloid
treating significant diseases such as cardiovascular diseases, diabetes stem cells that can differentiate into closely related cell types. While
and neurodegenerative diseases. Beside the use of stem cells in cell- e) unipotent stem cells such as dermatocytes are limitedly differ-
based therapies, stem cells applications are extended to the screening of entiated cells with the narrowest spectrum of differentiation cap-
new drugs and toxins and understanding birth malformation (Mitalipov abilities as it can only differentiate into single cell type, Fig. 1.
and Wolf, 2009). 2 On the basis of their sources, stem cells can be classified into a)
Stem cells are non-specialized, generic cells that are capable of self- embryonic stem cells (ESCs), b) adult stem cells and c) umbilical
copying and replication. In addition, they are able to differentiate and stem cells (USCs). ESCs are derived from embryos at a specific
produce specialized cells of different body tissues (Weissman, 2000). period nearly 4 or 5 days after fertilization. ESCs are pluripotent
Hence, stem cells are currently applied to replace the dysfunctional and cells, that are potentially not mortal and they maintain a normal
damaged cells (Weiss and Troyer, 2006). karyotype (Wobus and Boheler, 2005). Adult stem cells, are found
throughout the body, most of them are present in the bone marrow.
2. Classification of stem cells They are either unipotent, generating only single specific cell type or
multipotent capable of differentiation into limited types of cells such
1 Based on their differentiation potential, stem cells can be clas- as chondrocytes, osteoblasts and adipose cells. Because it’s found to
sified into (Zakrzewski et al., 2019): a) totipotent stem cells such as be superior for both differentiation potential and ability to divide in
those found in the zygote. They are the most powerful stem cells culture, adult stem cells are hope for cell therapy future. Adult stem
being capable of differentiation into cells of a fully functional living cells possess two special characteristics. The first one is the plasticity
organism. b) Pluripotent stem cells (PSCs) such as embryonic stem which is the ability of the cells to extend their potential beyond the
cells and induced pluripotent stem cells (iPSCs). These cells are tissue they are derived from. For example, Dental pulp stem cells
capable of differentiation into cells of the three germ layers. c) can develop into neural tissue besides developing into teeth tissue.

⁎
Corresponding author at: Faculty of Pharmacy, University of Tabuk-Kingdom of Saudi Arabia, Mansoura University, Egypt.
E-mail address: nelsherbiny@ut.edu.sa (N. Elsherbiny).

https://doi.org/10.1016/j.tice.2020.101351
Received 18 December 2019; Received in revised form 15 March 2020; Accepted 15 March 2020
Available online 19 March 2020
0040-8166/ © 2020 Elsevier Ltd. All rights reserved.
S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

Fig. 1. Types of stem cells based on their differentiation potential.

The second characteristic is the transdifferentiation where one cell 3. Advantage of umbilical cord stem cells (UCSCs)
type directly develops into another. For example, transdifferentia-
tion of hepatic cells into pancreatic cells and vice versa (Wagers and UCSCs possesses many advantages over bone marrow stem cells for
Weissman, 2004). Among adult stem cells, HSCs are the most transplants. First, UCSCs processing and collection is much easier and
characterized type of tissue-specific stem cells, and the only stem simpler. Indeed, the cord blood harvesting is quick and easy and the
cells in routine clinical use (Huss, 2000). following processing takes days to weeks (Broxmeyer and Smith, 2009).
In contrast, bone marrow stem cells matching, collection and processing
Umbilical cord (UC) was previously considered as biological waste, take longer time. It can take from weeks to months. Moreover, the
however it has become an accepted source of HSCs like those found in collection process of cord blood can be done either before or after
peripheral blood and bone marrow. The UC is formed of two arteries placental delivery and it is not painful to either mother or child, with a
and a vein surrounded by a gelatinous substance called Wharton’s jelly lesser need for stringent antigen typing as well as low risk for trans-
and covered by a simple epithelial layer. Wharton’s jelly protects the mission of infection. On the other hand, bone marrow transplants re-
blood vessels, prevents them from clumping and provides flexibility to quire the donor to be anesthetized, hospitalized with post-collection
the cord, Fig. 2. discomfort and pain. In addition, bone marrow transplantation and
collection of stem cells are more expensive. Importantly, the number of
stem cells per unit of volume in UC blood is greater than that found in

Fig. 2. Cross section in umbilical cord.

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

bone marrow. Further, UCSCs transplantation results in a lower rate of length of labor and labor stress and neonatal factors: gestational period,
graft-versus-host disease. This is attributed to the fact that they are also birth weight, length of UC (Mazzoccoli et al., 2016).
more tolerant of Human Leukocyte Antigen (HLA) mismatches than
those derived from the bone marrow. Also, unlike bone marrow, UCSCs 4.1. Collection
allow “off-the-shelf” use because of their capability to be stored in a
bank (Moise, 2005). Cord blood either collected prior to placental delivery (in utero) or
Nevertheless, the application of UCSCs faces some disadvantages after the placenta is delivered (ex utero). The in utero procedure is su-
such as slower engraftment than in bone marrow stem cell, limited perior in blood volume collected as the placenta is being compressed by
efficacy of autologous donation owing to hereditary disorders in addi- the uterus. Indeed, data from comparative studies suggest that higher
tion to banking issues (such as unknown length of storage, long-term volumes of cord blood and higher yields of total nucleated cells are
storage related cost, and quality control) (Shahrokhi et al., 2012). obtained via the in utero technique (Omori et al., 2010). Generally, the
Nowadays, UCSCs are used to replenish the patient's immune collection of cord samples is performed about five minutes prior to
system. UCSCs transplants can treat both malignant diseases as leu- placental expulsion using a syringe or plastic bag system for blood, and
kemia and non-malignant diseases as immune deficiencies, severe then the cord tissue is cut and saved (Wong et al., 2001). The procedure
aplastic anemia, and congenital disorders such as thalassemia and sickle of collecting the cord blood and tissue usually takes about 10 min. For
cell anemia (Roura et al., 2015a). Interestingly, in addition to their efficient collection procedure, 80−90 ml of cord blood and 20−25 cm
clinical use, cord blood is recently under intense experimental in- segment of the UC are recommended. There are many issues that should
vestigation in the preclinical models of disease pathophysiology that be taken in consideration during the collection of umbilical stem cells
can range from stroke, myocardial ischemia, to muscle regeneration including: getting a signed consent form the parents, sterility of the
(Mayani et al., 2019). whole procedure, clear family and obstetric medical history, checking
Umbilical stem cells were used for the first time in clinical practice for infectious diseases including hepatitis B and C, HIV and syphilis
in 1988 when Eliane Gluckman successfully made umbilical stem cells both in the medical history and during gestation, normal weight of
transplantation in Fanconi anemia 6-year-old boy (Gluckman et al., newborn with lack of signs of infection and congenital anomalies and
1989). In 1992, the first cord blood bank in the world was established. careful testing of the collected samples for microbial contamination.
It is important to mention that umbilical stem cells graft possesses During cord collection process, normal management of the third stage
better quality than the bone marrow one. Moreover, it has been found of labor should not be interfered, and the safety of mother and baby
that the amount of umbilical stem cells required for a successful should not be compromised. Obtaining an adequate volume of cord
transplantation is 10 times less than both peripheral blood cells and blood should not interfere with paying attentive care to mother and
bone marrow cells. Indeed, a volume of 80–120 mL blood of a single UC baby. Hence, cord blood collection is contraindicated in preterm birth,
is equivalent in its hematopoietic stem cells contents to 1200 mL of serious maternal medical or obstetric complications, such as massive
bone marrow (Gluckman, 2001; Revencu et al., 2013). Interestingly, hemorrhage stroke, cardiac arrest, eclampsia and perinatal asphyxia
Large body of evidence demonstrated that UC not only contains he- (Armson et al., 2015).
matopoietic progenitors, but also various other stem/progenitor cells
that include mesenchymal stromal cells (MSCs), unrestricted somatic
4.2. Processing methods
stem cells (USSCs), very small embryonic-like stem cells (VSELs), en-
dothelial progenitors and epithelial stem cells (Matsumoto and
Effective processing method should provide efficient recovery of
Mugishima, 2009).
both nucleated cells and progenitors. During processing, it is important
to reduce red blood cells. This facilitates banking of processed samples,
4. Collecting and processing the umbilical cord helps to overcome donor and recipient ABO or Rh incompatibility
concerns and results in higher cell viabilities and higher recoveries
Collection and processing UC samples are the main factors that upon thawing. Further, volume reduction procedures rationalize sto-
greatly affect both the volume and the yield of cells, Fig. 3. Other rage space and reduce required dimethyl sulfoxide (DMSO) in produced
factors affecting the volume and cell yield include maternal factors: age, cellular units (Solves et al., 2010). Routine quality testing includes
number of pregnancies and smoking; obstetric factors: cesarean section, evaluation of cell viability, total nucleated cells and number of CD34+

Fig. 3. Steps of umbilical cord stem cells banking process.

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

Fig. 4. Methods of umbilical cord stem cells processing.

Table 1
Comparison between umbilical cord stem cells processing methods.
Manual Semi-automated Automated

Examples Additives used for centrifugation include Ficoll, Percoll, Top and bottom system - AutoXpress Platform (AXP)
polygeline, gelatin, 6% hydroxyethyl starch - Sepax
- PrepaCyte-CB
Advantage - Cheap - Faster than manual - Short processing time,
- No needs for additives - Effective recovery mononuclear cells
(MNC)
- Replaced need for human manipulation
and additives.
- Automated process allows reduced risk of
contamination
- Increased reliability of results
Disadvantage - Slow - Red blood cell depletion is lower than - Expensive
- Use additives hydroxyethyl starch method
- Can’t be implemented in routine large scale cord blood - Recovery of mononuclear cells is less than
banking automated method

and CD45+ cells. Generally, the processing methods may be a) manual, Automated processing systems provide closed and standardized
b) semi-automated and c) automated (Takahashi et al., 2006), Fig. 4, procedure, short time for processing, effective recovery of mononuclear
Table 1. cells (MNC) in processed samples and replaced need for human ma-
The manual methods involve density gradient separation (Ficoll, nipulation and additives. Moreover, automated process allows reduced
Percoll, polygeline) by placing the anticoagulant-treated and diluted risk of contamination as well as increased reliability of results (Solves
sample on a preformed sucrose or cesium chloride gradient. During et al., 2013).
centrifugation, the high density erythrocytes and granulocytes sediment
to the bottom, while slowly sedimenting platelets and monocytes as 4.2.1. AutoXpress Platform (AXP)
well as lower density lymphocytes, are retained at the interface be- It is a closed processing set that reliably and individually collects
tween the plasma and Ficoll-Paque, where they can be further collected plasma, buffy coat and red blood cells in separate collection bags using
for separation of stem cells (Jaatinen and Laine, 2007). Other methods optical sensor technology. Of note, one important advantage of the AXP
apply gelatin or hydroxyethyl starch 6% (a strong sedimenting agent platform is that the processed cord blood units are richer in MNC than
causing rouleaux formation) for red blood cells sedimentation followed those processed by traditional procedures.
by two steps of centrifugation.
To simplify and shorten the process, blood fractionation was applied 4.2.2. Sepax
via the semi-automated top and bottom system. Indeed, semi-automated The Sepax system separates various cellular components through
method is faster with no need for exogenous additives. Briefly, the centrifugation of the full blood sample, then a light beam is utilized to
collected cord blood is centrifuged after transfer to a triple bag system. identify the density gradient between various cell layers. A rotating
High speed centrifugation is applied to separate the buffy coat with syringe technology allows both separation and transfer of cellular
simultaneous extraction of red blood cells at the bottom and fresh components (Lapierre et al., 2007). A major difference between AXP
plasma at the top while the leukocyte-platelet buffy coat layer is kept and Sepax devices is the use of HES, a sedimentation agent that is added
stable within the original extraction bag throughout the process. The to increase the initial blood volume and to enhance red blood cells
technique allows processing of the whole blood sample into three depletion and cell separation. The currently used Sepax protocol in-
fractions: plasma, red blood cells depleted -buffy coat and red cell cludes the addition of HES to the cord blood sample. This is in contrast
concentrate (Solves et al., 2009). to AXP protocol which currently does not involve HES addition. Indeed,

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

the Sepax system yield is better compared to AXP platform in terms of to bone marrow and peripheral blood stem cells and slower neutrophil
total nucleated cell recovery, CD34+ cell recovery and red blood cell recovery significantly limit the clinical application of cord blood HSCs.
depletion (Dazey et al., 2005). Hence, current efforts are being directed to expand HSCs. For example,
Mousavi et al. developed an ex vivo 3-Dimensional nano-fiber scaffold
4.2.3. PrepaCyte-CB that mimicked bone marrow microenvironment and resulted in higher
It provides sterile, antibody-based closed system that is capable of cell proliferation count, better adhesion and homing (Mousavi et al.,
removing about 99 % of unnecessary red blood cells and minimizes 2018). Another approach is the use of double-unit cord blood trans-
contamination during processing. The system is based on one‐step re- plantation for adults and larger adolescents (with body weight ≥ 50 kg)
agent that facilitates red blood cells aggregation and rapid sedimenta- with hematological malignancies (Zheng et al., 2018). Nevertheless, the
tion with the desired cell fraction left in the supernatant (Basford et al., proliferative capacity of the HSCs in a cord blood unit is superior to
2010). both adult bone marrow and peripheral blood and the cells demon-
Following processing of cord blood, the expected volume available strated increased engraftment potential compared to those from bone
for cryopreservation ranges from 25 to 80 ml based on the method marrow or peripheral blood (Benito et al., 2004).
utilized. Nevertheless, the cell number is a superior criterion and Beside low frequency, many challenges exist in isolation of HSCs
smaller sample volume may contain as many clinically useful cells as a with high purities and yields such as small sample volumes and the fact
larger one (Basford et al., 2009). that the quality and viability of cells can be variable between different
samples (Jaatinen and Laine, 2007). HSCs can be separated from pro-
5. Banking cessed cord blood by immunomagnetic separation and fluorescent-ac-
tivated cell sorting (FACS).
It is noteworthy that one of the most important advantages of UCSCs Immunomagnetic cell sorting is based on the existence of HSCs
is the capability of banking of the harvested cells for future use. There surface antigens, or the lack of expression of lineage-specific antigens.
are three types of banks, public, private and hybrid. The public banks Paramagnetic microbeads conjugated to monoclonal antibodies for
allow storage of altruistic units from donors to be used by any potential specific surface markers are used to label HSCs. The labeled cells are
HLA-matched recipient. However, private or family banks store units to further enriched on a column placed in a magnetic field where un-
be used exclusively by the donor or his/her matched relatives. Hence, labeled cells pass through the column and labeled cells retain.
private banks charge the family for processing and storage of the cord Following removal from the magnet, the retained (required) cells can
blood samples. Hybrid banks possess both public and private UC bank be eluted from the column (Kekarainen et al., 2006).
(UCB) storage options (Dessels et al., 2018). Of note, banking of cord Fluorescent-activated cell sorting (FACS) is the main technique
blood has been markedly developed. Globally, there are about 800,000 currently used for isolation and characterization of stem cells, including
cord blood units stored in public banks, while in private banks, more HSCs. It is a flow cytometry technique that relies on two characteristic
than 4 million units are being stored (Mayani et al., 2019). Cord blood features of HSCs. The first strategy is using fluorochrome-conjugated
banking, regardless of whether it is public or private, is a business antibodies against specific cell surface markers of HSCs, and the second
operation that hugely cost the public health care or the patient, re- one is utilizing the ability of HSCs to efflux certain fluorescent dyes (Lin
spectively. However, cord blood banks should focus on the quality of and Goodell, 2011).
the cord blood unit and hence improved outcome of the cord blood
transplant rather than focusing on quantity. Compared to public banks, 6.2. Endothelial progenitors
private cord blood banks are less regulated for quality control, under-
used for treatment (the use rate of banked cord blood unit is at least 30- Endothelial progenitors are precursor cells that possess the ability to
fold greater in public cord blood banks compared to private ones), and differentiate into mature endothelial cells. Endothelial progenitors were
more expensive. Thereby, donation to public institutions is strongly implicated in various disease conditions such as myocardial ischemia
supported by most professional organizations with the exception in and infarction and angina, stroke, atherosclerosis, diabetic vascular
instances when a family has a sibling in need of a transplant or has a complications, pulmonary arterial hypertension, wound healing and
genetic risk of producing a sibling with a transplantable disease (Lubin tumor angiogenesis (Janic and Arbab, 2012). In addition to HSCs, UC
and Shearer, 2007). blood has been reported to be a rich source of endothelial progenitor
cells that can be used for endothelial progenitor cells -based vascular-
6. Umbilical cord stem cells culturing ization therapies. Indeed, cord blood contains significantly higher fre-
quency of endothelial progenitors than peripheral blood or bone
It is preferable to store both cord blood and cord tissue to facilitate marrow. Au et al. (Au et al., 2008) reported that UC blood derived
maximum recovery of all stem cells types. UC can be utilized for iso- endothelial progenitor cells develop stable normal-functioning blood
lation of epithelial, hematopoietic and mesenchymal cells. Cord blood vessels in terms of blood flow, selective permeability to macro-
vessels, intravascular and perivascular zones, subamniotic zone and molecules and cytokine-induced leukocyte-endothelial interactions.
amniotic epithelium are all valuable sources for stem cells, Fig. 5, The isolation of endothelial progenitor cells is complicated due to the
Table 2. Indeed, the UC blood contains HSCs that can be utilized for lack of a single specific surface marker. However, most applications of
generation of various blood cells. Moreover, MSCs were successfully endothelial progenitor cells in vasculogenesis have utilized endothelial
isolated from Wharton’s jelly, amniotic fluid and membrane, and cord progenitor cells differentiated from CD34+/ CD133+/ VEGFR2+
lining (Cardoso et al., 2012), where epithelial cells were isolated from mononuclear cells using medium that favor endothelial differentiation
the internal and external layers of the UC (Saleh and Reza, 2017). (Lee et al., 2013; Janic and Arbab, 2012).

6.1. Hematopoietic stem cells (HSCs) 6.3. Mesenchymal stromal cells (MSCs)

Transplantation of HSCs is currently applied as potentially curative MSCs are defined as multipotent cells, of mesodermal origin that
therapy for various hematological disorders of blood, immune system possess the following characteristics: ability to differentiate into at least
and bone marrow. UC blood can be utilized to make various blood cells osteocytes, adipocytes or chondrocytes, capability of adherence to
including red and white blood cells and platelets. Compared to a bone plastic surfaces, and surface expression of specific antigen markers
marrow graft, the number of functional HSCs in a cord blood unit is 10 (Dominici et al., 2006). Generally, two methods are currently used for
times less. Indeed, decreased number of total nucleated cells compared the isolation of MSCs from the UC: enzymatic digestion and explants

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

Fig. 5. Types of cells isolated from umbilical cord stem cells.

technique. In enzymatic method, the UC tissue is treated with an en- cells compared to fibroblasts and keratinocytes (Giorgetti et al., 2010).
zyme such as collagenase, trypsin, dispase and hyaluronidase that re-
leases cells into the incubating solution via disrupting the collagen 7. Applications
matrix. This is followed by collection of the solution, centrifugation and
separation of cells from the supernatant. The cells are then cultured UCSCs therapy carries immense potential for treating a number of
with stem cell media. While in explants method, the dissected UC tissue human diseases. The application of these cells in regenerative medicine
is fragmented and transferred to a tissue culture dish containing media and organ grafts holds tremendous promise to fulfill the largely unmet
that stimulates stem cells propagation. The tissue adheres to the bottom need for organ transplants and to improve the quality of life for millions
of the culture dish and the stem cells migrate from the cord onto the of patients (Fig. 6).
dish surface. The tissue can be removed when the cells are visibly ad-
hering to the surface of the plastic dish (Mori et al., 2015). Omitting the
7.1. Stem cells in treatment of hematological diseases
proteolytic enzymes and presence of cells in companion with a piece of
their tissue origin in the primary culture in explant method leads to
Hematological diseases are diseases that affect blood cells and
successful and high yield isolation. Indeed, explant method- derived
blood-forming organs. Hematopoietic stem/progenitor cells derived
MSCs have shown superiority to enzymatic derived methods in terms of
from UC have been widely applied in various hematological diseases
cellular yield and viability, concentration of basic fibroblast growth
including sickle cell anemia (Tanhehco and Bhatia, 2019), aplastic
factor, successful differentiation into mesodermal lineages in addition
anemia (Xu et al., 2018) thalassemia (Li et al., 2018), Leukemia
to reduced cost and contamination risk. However, in explant method, a
(Dolstra et al., 2017). The pioneering of the first cord transplant leads to
longer time is required to obtain cells in primary culture initial step
much progress in the clinical application of UC blood stem cells for
compared to enzymatic method (Hendijani, 2017).
HSCs transplantation. Indeed, over two decades, UC blood stem cells
were indicated successfully for pediatric patients with hematological
6.4. Epithelial stem cells malignancies (Kurtzberg et al., 2008), nonmalignant hematological
diseases (Boelens et al., 2013) and adult patients with hematological
The UC lining is the richest source for epithelial stem cells. UC malignancies (Laughlin et al., 2001).
epithelial stem cells are currently under investigation for a wide range
of clinical applications including wound healing and ocular surface
7.2. Stem cells in treatment of cardiovascular diseases
regeneration (Saleh and Reza, 2017). UC lining epithelial cells are
characterized by pluripotency, similar cytokeratin pattern to human
Cardiovascular diseases (CVD) include hypertension, coronary ar-
epidermis and immunosuppressant properties that play a crucial role in
tery disease, stroke, and congestive heart failure. CVD often result in
engraftment promotion and rejection rate lowering via modulating the
the deprivation of oxygen supply to heart cells known as cardiomyo-
patient’s immune system (Bickenbach, 2005). UC-derived epithelial
cytes, leading to cardiomyocyte damage, and narrowing of the blood
stem cells can form a stratified epithelial layer using collagen gels po-
vessels that supply the heart. The adult myocardium contains a small
pulated with fibroblasts as feeder cells for seeding (Ziaei et al., 2017).
population of cardiac stem cells with the ability to differentiate into
cardiomyocytes and some other cell types. Restoration of damaged
6.5. Induced pluripotent stem cells cardiomyocytes and vascular endothelial cells (cells that form the lining
of the blood vessels) by stem cell therapy appears to be a promising
Induced pluripotent stem cells are produced from somatic cells that treatment for this ailment. Preclinical studies reported that using cord
have been exposed to reprogramming into an embryonic-like plur- blood MSCs inhibited apoptosis of cardiomyocyte, stimulated angio-
ipotent state with unlimited capacity to develop various types of human genesis, suppressed myocardial inflammation and displayed therapeutic
cells needed for therapeutic purposes. Cord blood CD133 + cells have activity in experimental models of dilated cardiomyopathy. To date, UC
been reported as a safe and fast source for induced pluripotent stem blood cells and MSCs are less studied clinically for cardiovascular

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

regeneration (Roura et al., 2015b). However, a study by Kim et al. re-

Induced pluripotent stem
ported disappearance of ischemic rest pain, increased number and size

SSEA-4, Oct-3/4, Nanog

of digital capillaries, reduced vascular resistance and improved per-
ipheral circulation in four patients with Buerger’s disease transplanted
with UCMSCs (Kim et al., 2006). Further, Ichim et al. reported clinical
improvement in a dilated cardiomyopathy patient treated with in-
travenous allogeneic MSCs and expanded UC blood (Ichim et al., 2008).
cells

7.3. Stem cells in bone regeneration

p63, Cytokeratins 18, 19, CD44, CD 54,

Damage in bone structure results from imbalance in the bone re-

modeling process (between osteoblasts and osteoclasts actions) and
leads to diseases such as osteoporosis. Congenital malformations, tumor
resections, fractures, trauma as well as diseases such as arthritis can
result in bone damage. It was demonstrated that MSCs obtained from
Epithelial stem cells

human UC blood could improve trabecular and bone formation para-

meters and prevent bone loss in ovariectomized mouse (An et al.,
2013). In addition, Hong et al. reported that human UC blood derived-
MSCs enhanced bone regeneration in osteoporotic rat model suggesting
CD104

their application as promising alternative stem cell therapy for osteo-

porosis (Hong et al., 2018).
Mesenchymal stromal cells

7.4. Stem cells in the treatment of eyesight diseases

CD105, CD73, CD90

Stem cell technology is currently being explored to restore the gift of

sight to patients, who lost their vision due to various reasons. The re-
generative capacity of stem cells makes them an ideal source for the
derivation of specialized cells. These cells could be used to repair da-
maged portions of the eye that cause impairment or complete loss of
vision. The retina, in particular is often considered an excellent target
share several surface markers with Hematopoietic stem cell such as CD34, KDR, and

for stem cell therapy, as it can be easily monitored for improvements of

the post treatments. Indeed, intravitreal injection of neural stem cells
developed from human UC-derived MSCs increased the number of
surviving retinal ganglion cells and alleviated diabetic retinopathy-as-
sociated neurodegeneration in rats (Zhang et al., 2017). Moreover, in a
mice model of traumatic optic neuropathy, an important cause of severe
vision loss, human UC blood derived-MSCs favorably modulated oxi-
dant-apoptotic status, improved histological structure and enhanced
expression of growth factors in retinal tissue (Mohamed et al., 2017).

7.5. Stem cells in the treatment of diabetes

Types of cells isolated from umbilical cord stem cells and their surface markers.

With advances in stem cell technology, there is a great interest in

developing β-cells from stem cells, thereby helping the damaged pan-
creatic environment to repopulate itself and restore full functionality.
MSCs from the human UC matrix are currently under investigation to
Endothelial progenitors

treat diabetes. UCMSCs lack or exhibit very low levels of cell surface
Tie-2 and VE-cadherin

markers that are detected by the immune system. This underlying

ability to remain undetected by the immune system makes these cells
ideal in the treatment of type 1 diabetes. They can also stimulate β-cells
by secreting growth factors such as insulin growth factor-1 (IGF1)
(Zhou et al., 2015). Moreover, plenty of regulatory T cells (Tregs) can
be found in UC blood. These cells hold the promise in their ability to
restore peripheral tolerance toward pancreatic islet β cells through
Hematopoietic stem cells

suppressing the autoreactive T cells (He et al., 2015). Also, Boroujeni

and Aleyasin reported the ability of UCMSCs to differentiate into in-
sulin-producing cells in vitro, emphasizing their use as viable resource
CD34, CD133

in cell-based therapy for treatment of type 1 diabetes (Niki Boroujeni

and Aleyasin, 2014). Besides, cord lining epithelial cells transduced
with a modified human proinsulin gene differentiated into insulin
producing cells when transplanted intraperitoneally into type 1 diabetic
Surface markers

mice, resulting in significant hypoglycemic effect. Allogeneic UCMSCs

Type of cells

have also been transplanted in type 2 diabetic patients and were able to
improve islet cell function in these patients. The therapeutic benefit
Table 2

mediated by MSCs largely relies on the contribution of the secreted

growth factors and cytokines rather than on their potential for

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

Fig. 6. Applications of umbilical cord stem cells.

differentiation to islets (Guan et al., 2015). Indeed, UCMSCs were re- progression of disease has shown more promising results for HD com-
ported to ameliorate insulin resistance in type 2 diabetic rats by sup- pared to neuronal replacement. Indeed, UCMSCs dampened oxidative
pressing inflammation (Sun et al., 2017), inhibition of β-cell apoptosis stress-induced neuronal death and improved motor dysfunction and
and restoration of the insulin-secreting function (Sun et al., 2018). striatal atrophy in experimental rat model of HD (Ebrahimi et al.,
2018).
7.6. Stem cells in treatment of neurodegenerative disorders
7.6.3. Alzheimer’s disease (AD)
Neurodegenerative disorders are a term used for a wide range of AD is neuro-progressive characterized by loss of cerebral neurons
acute and chronic conditions, in which neurons and glial cells in the and synapses. Therapies based on enhancing cholinergic function via
brain and the spinal cord are lost. Generating fresh nerve cells based on the use of acetylcholinesterase inhibitors, provide limited effects with
stem cells therapy offers a potential treatment for these diseases. The only partial and temporary attenuation of symptoms. It is now evi-
main approaches applied in stem cell therapy for neurodegenerative denced that diffusible factors released by stem cells are beneficial in
disorders are: improving the survival of degenerating and aged human brain neurons.
In this context, MSCs from the UC have been used in the treatment of
a Achieving stem cell-based nerve cell replacement and repair in the experimentally induced AD. Neuroprotective factors produced by these
CNS. In this case, the transplanted stem cells differentiate into nerve cells attenuate oxidative stress and promote hippocampal neurogenesis
cells and thereby help in reconstituting healthy nerve tissue. in experimental mouse model, thus providing a viable therapy for AD
b Stem cell therapy can also be used to modulate inflammation in- treatment (Cui et al., 2017).
volved in the disease process thereby delaying the progress of the
disease. 7.6.4. Amyotrophic lateral sclerosis (ALS)
c Modulation of the host environment by paracrine factors that are ALS is a rare and progressive adult-onset neurodegenerative disease
released from transplanted stem cells. These factors can encourage that may lead to fatal paralysis. The pathogenesis of ALS involves de-
the growth of stem cells present in the brain, thus letting the brain generation of neurons that control voluntary movement in the brain-
repair itself. stem, cerebral cortex and the spinal cord. Administration of human UC
blood cells in experimental mice models of ALS generated growth
7.6.1. Parkinson’s disease (PD) factor-releasing cells, immunomodulatory cells and functional support
PD is caused by the loss of cells that secrete dopamine. cells such as glia, or GABAergic interneurons which in turn enhanced
Transplanting dopamine synthesizing cells is being considered as an motor neuronal survival and activity of existing motor neurons (Galieva
alternative approach for restoring the damage. UCMSCs are considered et al., 2017).
an unlimited and inexpensive reservoir of differentiable cells towards
functional dopaminergic neurons, making them ideal candidates for 7.7. Stem cell therapy in stroke
treatment of PD patients. Nevertheless, further investigations as well as
controlled clinical trials are needed to confirm the efficacy of UCMSCs Stroke is a sudden death of brain cells in a particular area caused by
for therapeutic applications in medical practice. Interestingly, UCMSCs interrupted blood flow. The application of stem cells in the treatment of
were found to possess a greater potential of differentiation into neuron- stroke has been pursued with a hope to find a cure. A recent clinical
like cells in vitro compared to bone marrow MSCs (Boroujeni and trial showed that intravenous infusion of UC blood improved functional
Gardaneh, 2017; Kang et al., 2013). outcomes in patients with ischemic stroke (Laskowitz et al., 2018).
Interestingly, proteomic analysis of the peri-infarction region in is-
7.6.2. Huntington’s disease (HD) chemic stroke mice following UCMSCs transplantation revealed upre-
HD is characterized by deposition of aggregated huntingtin protein, gulation of proteins that are known as crucial players in pathologic and
which results in neuronal dysfunction and degeneration. Recently, physiologic processes in the human brain (He et al., 2016).
suggested HD treatment strategies are based on stem cells therapy that
either target dysfunctional and dead neuronal cells for replacement, or 7.8. Stem cell therapy in autism
vulnerable neuronal cells for protection. However, using stem cells to
deliver neurotrophic factors and for neuroprotection to prevent Autism spectrum disorders (ASDs) are group of neurodevelopmental

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S.M. Alatyyat, et al. Tissue and Cell 65 (2020) 101351

disorders that improperly impact behavior, verbal and non-verbal progenitor cells from human umbilical cord blood and adult peripheral blood to form
communication and social interaction. When affect children, they dis- functional long-lasting vessels. Blood 111 (3), 1302–1305.
Basford, C., Forraz, N., Habibollah, S., Hanger, K., McGuckin, C.P., 2009. Umbilical cord
play repetitive behavior and speech patterns. They may also suffer blood processing using Prepacyte‐CB increases haematopoietic progenitor cell
anxiety, attention-deficit/hyperactivity disorder, sleep and gastro- availability over conventional Hetastarch separation. Cell Prolif. 42 (6), 751–761.
intestinal disorders, intellectual disability and motor impairments. Basford, C., Forraz, N., Habibollah, S., Hanger, K., McGuckin, C., 2010. The cord blood
separation league table: a comparison of the major clinical grade harvesting techni-
Recently, UCMSCs have been used safely for treatment of autism in ques for cord blood stem cells. Int. J. Stem Cells 3 (1), 32.
children due to their immune-modulatory and anti-inflammatory Benito, A.I., Diaz, M.A., Gonzalez-Vicent, M., Sevilla, J., Madero, L., 2004. Hematopoietic
properties. The administration of repeated‐dose of UCMSC infusions stem cell transplantation using umbilical cord blood progenitors: review of current
clinical results. Bone Marrow Transplant. 33 (7), 675.
resulted in reduced macrophage‐derived chemokine and activation‐re- Bickenbach, J.R., 2005. Isolation, characterization, and culture of epithelial stem cells.
gulated chemokine and improved Autism Treatment Evaluation Epidermal Cells. Humana Press, pp. 97–102.
Checklist (ATEC) and the Childhood Autism Rating Scale in children Boelens, J.J., Aldenhoven, M., Purtill, D., Ruggeri, A., DeFor, T., Wynn, R., et al., 2013.
Outcomes of transplantation using various hematopoietic cell sources in children
diagnosed with ASD (Riordan et al., 2019). Indeed, UC blood infusion
with Hurler syndrome after myeloablative conditioning. Blood J. Am. Society
improved socialization in children with autism with no serious adverse Hematol. 121 (19), 3981–3987.
events suggesting its safety for further large scale tightly controlled Boroujeni, M.E., Gardaneh, M., 2017. Umbilical cord: an unlimited source of cells dif-
trials (Chez et al., 2018). ferentiable towards dopaminergic neurons. Neural Regen. Res. 12 (7), 1186.
Broxmeyer, H.E., Smith, F.O., 2009. Cord blood hematopoietic cell transplantation.
Thomas’ Hematopoietic Cell Transplantation. Wiley-Blackwell, Malden, Mass, USA,
7.9. Stem cells in wound healing pp. 559–576.
Cardoso, T.C., Ferrari, H.F., Garcia, A.F., Novais, J.B., Silva-Frade, C., Ferrarezi, M.C.,
Ferrarezi, M.C., Andrade, A.L., Gameiro, R., 2012. Isolation and characterization of
Stem cells are known to tremendously influence normal cell and Wharton’s jelly-derived multipotent mesenchymal stromal cells obtained from bovine
tissue repair/regeneration to treat chronic wounds. Self-renewing umbilical cord and maintained in a defined serum-free three-dimensional system.
characteristics and multipotent differentiation potential of stem cells BMC Biotechnol. 12 (1), 18.
Chez, M., Lepage, C., Parise, C., Dang‐Chu, A., Hankins, A., Carroll, M., 2018. Safety and
make them ideal candidates for the treatment of chronic wounds. Stem observations from a placebo‐controlled, crossover study to assess use of autologous
cells can differentiate into new cells, secrete trophic factors, promote umbilical cord blood stem cells to improve symptoms in children with autism. Stem
angiogenesis, modulate the immune system, improve wound closure, Cells Transl. Med. 7 (4), 333–341.
Cui, Y., Ma, S., Zhang, C., Cao, W., Liu, M., Li, D., Lv, P., Xing, Q., Qu, R., Yao, N., Yang,
and also help in the development of new extracellular matrix (ECM). B., Yang, B., 2017. Human umbilical cord mesenchymal stem cells transplantation
The use of stem cell therapy in burn injuries and wound healing aim improves cognitive function in Alzheimer’s disease mice by decreasing oxidative
improved the rate and quality of healing. This was accompanied by stress and promoting hippocampal neurogenesis. Behav. Brain Res. 320, 291–301.
Dazey, B., Duchez, P., Letellier, C., Vezon, G., Ivanovic, Z., 2005. Cord blood processing
avoiding scar tissue formation and dampening infections by immune
by using a standard manual technique and automated closed system“ Sepax”(Kit CS-
response modulation (Huang and Burd, 2012). Wharton's jelly- derived 530). Stem Cells Dev. 14 (1), 6–10.
MSCs have been applied as valuable source in repair of chronic ulcers. Dessels, C., Alessandrini, M., Pepper, M.S., 2018. Factors influencing the umbilical cord
Hence they markedly accelerated the healing effect in chronic diabetic blood stem cell industry: an evolving treatment landscape. Stem Cells Transl. Med. 7
(9), 643–650.
wounds in a randomized clinical trial (Hashemi et al., 2019). In this Dolstra, H., Roeven, M.W., Spanholtz, J., Hangalapura, B.N., Tordoir, M., Maas, F.,
context, UCMSCs were found superior to fibroblasts in stimulating Leenders, M., Bohme, F., Kok, N., Trilsbeek, C., Paardekooper, J., van der Waart, A.B.,
diabetic wound healing in vitro (Jung et al., 2018). Moreover, MSCs of Westerweel, P.E., Snijders, T.J.F., Cornelissen, J., Bos, G., Pruijt, H.F.M., de Graaf,
A.O., van der Reijden, B.A., Jansen, J.H., van der Meer, A., Huls, G., Cany, J., Preijers,
cord blood origin showed effective healing of burn injuries via inducing F., Blijlevens, N.M.A., Paardekooper, J., 2017. Successful transfer of umbilical cord
efficient skin regeneration in burned patients (Abo-Elkheir et al., 2017). blood CD34+ hematopoietic stem and progenitor-derived NK cells in older acute
myeloid leukemia patients. Clin. Cancer Res. 23 (15), 4107–4118.
Dominici, M.L.B.K., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F.C., Krause,
8. Conclusion D.S., Deans, R., Keating, A., Prockop, D.J., Horwitz, E.M., 2006. Minimal criteria for
defining multipotent mesenchymal stromal cells. The International Society for
Cord blood provides countless stem cells of both hematopoietic and Cellular Therapy position statement. Cytotherapy 8 (4), 315–317.
Ebrahimi, M.J., Aliaghaei, A., Boroujeni, M.E., Khodagholi, F., Meftahi, G., Abdollahifar,
nonhematopoietic phenotype. The therapeutic utilization of these cells
M.A., Ahmadi, H., Danyali, S., Daftari, M., Sadeghi, Y., 2018. Human umbilical cord
is widely extended both in children and adults for treatment of various matrix stem cells reverse oxidative stress-induced cell death and ameliorate motor
hematologic and non-hematologic diseases with successful performance function and striatal atrophy in rat model of Huntington disease. Neurotox. Res. 34
(2), 273–284.
of more than 40,000 UC transplants (Mayani et al., 2019). However,
Galieva, L.R., Mukhamedshina, Y.O., Arkhipova, S.S., Rizvanov, A.A., 2017. Human
detailed understanding of molecular mechanisms controlling stem cell umbilical cord blood cell transplantation in neuroregenerative strategies. Front.
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to overcome the limited cell numbers and naivety of the cells. To meet Giorgetti, A., Montserrat, N., Rodriguez-Piza, I., Azqueta, C., Veiga, A., Belmonte, J.C.I.,
2010. Generation of induced pluripotent stem cells from human cord blood cells with
these challenges, further researches on basic and molecular biology of only two factors: Oct4 and Sox2. Nat. Protoc. 5 (4), 811.
UCSCs are needed, novel clinical trials should be developed and im- Gluckman, E., 2001. Hematopoietic stem-cell transplants using umbilical-cord blood. N.
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context, additional efforts should be applied to solve persistent con- tion in a patient with Fanconi’s anemia by means of umbilical-cord blood from an
troversy on the most appropriate and economically sustainable model HLA-identical sibling. N. Engl. J. Med. 321 (17), 1174–1178.
to maximize the quality and yield of stored UC product. Guan, L.X., Guan, H., Li, H.B., Ren, C.A., Liu, L., Chu, J.J., Dai, L.J., 2015. Therapeutic
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