Cord Blood Stem Cell: A Future Lifeline in Therapeutic Management

¹Manjinder Sharma, ²Milindmitra Lonare and ¹Rajesh Kumar Sharma

¹Division of Veterinary Physiology and Climatology

²Division of Veterinary Pharmacology and Toxicology

Indian Veterinary Research Institute, Izzatnagar,

Bareilly 243 122, India

Corresponding Author (Present :

Dr. Manjinder Sharma

Stem cell

Stem cells have unlimited capacity of self renewal and can differentiate into any kind of cell in the body. The stem cells found in cord blood are the building blocks of blood and immune system and most readily replicate into:

Red Blood Cells - which carry oxygen to all the cells in the body
White Blood Cells - which fight infection, and
Platelets - which aid in clotting in the event of injury

There are three sources where stem cells of the blood are commonly found:

Bone Marrow
Peripheral Blood
Umbilical Cord Blood

Umbilical cord blood (UCB), which is also called "placental blood," is the blood that remains in the umbilical cord and placenta following birth and after the cord is cut. The ability of cord blood stem cells to differentiate or change into other types of cells in the body is a new discovery that holds significant promise for improving the treatment of some of the most common diseases such as heart diseases, stroke and Alzheimer's.

In the past, umbilical cord blood samples have usually been discarded following birth. But scenario is changing rapidly as umbilical cord blood transplantation (UCBT) has recently been fastened up in an increasing number of adult patients. People are going for cord blood banking to avoid complication which may occur in future. Umbilical cord blood is known as a rich source of hematopoietic stem cells (HSC), which makes it a valuable alternative to bone marrow transplantation in hematology and oncology. Although cord blood is mainly used for the treatment of leukemia and other blood diseases, the therapeutic potential of UCB cells can go beyond blood system therapy. In addition to the HSC, a variety of different stem cell types have been identified within UCB which are mesenchymal stem cells (MSC), endothelial stem cells (ESC) and many more yet to be characterized in the cord blood.

Cord blood stem cells in clinical application - advantages and disadvantages

UCB has now emerged as an attractive source of stem cells for research and clinical application in treating a variety of diseases due to the following advantages over other stem cell sources:

Non-invasive collection without any risk for the donor.
Abundance. More than 100 million births annually worldwide make the UCB a readily available source of stem cells.
Rising number of public and private banks, which can store huge quantities of cord blood units, allow an optimal HLA match for the allogeneic or potentially autologous transplantation.
Do not involve ethical issues.

The biological advantages of UCB stem cells are even more apparent. Cord blood is collected immediately after the birth, which means that UCB stem cells are among the youngest types of cell that can be isolated from an individual. This is important, as cells from adult donors may have an impaired DNA quality caused by environmental and endogenous factors which also include aging. Moreover, the UCB cells carry a lower risk of viral contamination due to the minimal exposure of donor babies to viruses during prenatal life.

A disadvantage associated with therapeutic application of UCB, which is common with other allogeneic cell-based therapies, is the potential to induce graft-versus-host disease (GVHD), which may develop as a result of immune cell transplantation to the recipient. Bone Marrow transplantations (BMT) subjects face same even if a high degree of HLA match is there. However, compared to BMT, the incidence of GVHD is lower in UCB transplantation, which could be due to the lower number of T-cells, immaturity of B-cells and decreased function of dendritic cells. The depletion of lymphocytes and other immune cells could further limit the incidence of GVHD. However, the elimination of some immune cells may impair the establishment of cell chimerism, which is speculated to be a crucial mechanism for the achievement of a long lasting tolerance of the host immune system to transplanted cells.

Therapeutic uses of cord blood stem cells

The presence of relatively mature hematopoietic progenitor cells (HPC) in human umbilical cord blood was demonstrated by Knudtzon in 1974. About ten years later, Ogawa and colleagues documented the presence of primitive HPC in UCB. However, it was not until 1989 that experimental and clinical studies were published indicating that human UCB could be used in clinical settings.

Broxmeyer and coworker (1989) experimentally cleared that umbilical cord blood is a rich source of hematopoietic stem/progenitor cells (HSPC). That same year, Gluckman and coworker reported on the first hematopoietic cell transplant in which UCB was used instead of bone marrow (BM) as the source of hematopoietic cells. They were able to reconstitute the hematopoietic system of a child with Fanconi anemia by means of UCB from an HLA-identical sibling (Gluckman et al., 1989). Since then, there has been an expanding interest in the use of UCB as an alternate source of HSPC for transplantation. To date, more than 500 of these transplants have been performed worldwide. Umbilical cord blood stem cell transplants are less prone to rejection than either bone marrow or peripheral blood stem cells. This is probably because the cells have not yet developed the features that can be recognized and attacked by the recipient's immune system. Also, because umbilical cord blood lacks well-developed immune cells, there is less chance that the transplanted cells will attack the recipient's body, a problem called graft versus host disease. Both the versatility and availability of umbilical cord blood stem cells makes them a potent resource for transplant therapies.

Umbilical cord blood represents other sources of multipotent stem cells that might be used for generating diverse differentiated cell types (Ishikawa et al., 2003; Cohen and Nagler, 2004; Ortiz-Gonzalez et al., 2004; Perillo et al., 2004; Sanmano et al., 2005). Moreover, the neonatal cord blood contains a primitive subpopulation of CD3 HSCs that shows a higher hematopoietic expansion capacity in the presence of FLT-3 ligand, KIT ligand and thrombopoietin (TPO) as compared with their counterpart in adult mobilized peripheral blood (MPB) (Tanavde et al., 2002). In this matter, the elevated levels in plasma concentrations of testosterone, estriol, insulin-like growth factor-1 (IGF-1), and IGF binding protein-3, which were detected in human UCB from 40 women, have been associated with a high proliferative potential of CD34/CD38 cells and colony-forming unit granulocyte-macrophage (Baik et al., 2005). Several works have also revealed the possibility of differentiating the UCB stem cells into diverse functional cell progenitors, including hematopoietic cell lineages, dendritic cells, neural cell progenitors, hepatocytes, pancreatic cells, and endothelium under specific culture conditions in vitro and in vivo (Ishikawa et al., 2003; Ortiz-Gonzalez et al., 2004). For instance, the xenogeneic transplantation of CD34 or CD45 human cord blood cells in the neonatal nonobese diabetic (NOD)/SCID/ 2-microglobulinnull animal mice models in vivo have revealed that these cells give rise to human hepatocytes showing morphological characteristics comparable to those of mouse hepatocytes (Ishikawa et al., 2003). Significantly, the results from reverse transcription-polymerase chain reaction analyses have also confirmed that the expression of human albumin mRNA occurred in these human engrafted cells, suggesting that they have effectively acquired the functional properties associated with mature hepatocytes.

Furthermore, the trans-differentiation of human mononuclear cell population from UCB into insulin producing-like cells that express specific markers of developing pancreas such as nestin, cytokeratin (K8), K18, and diverse transcription factors (Isl-1, Pdx-1, Pax-4, and Ngn-3), has also been performed in medium containing fetal calf serum (Pessina et al., 2004). Similarly, the differentiation and enrichment of CD1, CD83, CD11c and CDw123 dendritic cells from UCB have also been carried out in vitro by the culture of cells in a medium containing diverse cytokines, such as granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin-3 (IL-3), recombinant human stem cell factor (SCF), and erythropoietin (EPO), for 2– 4 weeks (Lian et al., 2004). Hence, these dendritic cells may be used as an adjuvant in immunotherapy for diverse disorders and cancers. In addition, human UCB also contains a more primitive subpopulation of mesenchymal stem cells than adult BM, the immature cells of which express adhesion molecules, such as CD13, CD29, CD44, CD90, CD95, CD105, CD166, and major histocompatibility complex class, but not the antigens of hematopoietic differentiation, such as CD34 (Erices et al., 2003; Chang et al., 2006). These mesenchymal stem cells can also differentiate into multiple lineages, including progenitors with bone, fat, and neural markers, under specific conditions in vitro. Interestingly, it has been reported that the systemic infusion of mesenchymal stem cell progenitors in immunodeficient mice resulted in their engraftment in BM, as well as in other diverse tissues, including the heart, teeth, and spleen (Erices et al., 2003). Thus, it appears that the differentiation of UCB stem cells into tissue-specific adult stem cell progenitors might constitute an alternative strategy for cellular therapies of diverse disorders.

Table 1: Disorders Treated With Cord Blood Stem Cells
Disorder	Number Treated	Outcome	Reference
Hurler's syndrome	20	17 of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral-blood alpha-L-iduronidase activity	(Staba et al., 2004)
Duchenne muscular dystrophy	1	On 42nd day, physical examination revealed obviously improvement in walking, turning the body over, and standing up	(Zhonghua et al., 2005)
Malignant infantile osteopetrosis	1	Normalization of spine bone mineral density	(Jaing et al., 2008)
Buerger's disease	4	Ischemic rest pain suddenly disappeared. Digital capillaries were increased in number and size	(Kim et al., 2006)
Spinal Cord Injury	1	Improved sensory perception and movement in the SPI patient's hips and thighs within 41 days of cell transplantation. Regeneration of the spinal cord at the injured site	(Kang et al., 2005)
Krabbe's disease	25	Progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills in patient subset	(Escolar et al., 2005)
Omenn syndrome	1	T cell reconstitution	(Tomizawa et al., 2005)
Non-healing wounds	2	Accelerated healing	(Valbonesi et al., 2004)
Refractory anemia	3	All patients are alive and free of disease at between 17 and 39 months after cord blood administration	(Ooi et al., 2005)
Diamond-Blackfan anemia	1	Successful seroconversion to vaccines (diphtheria, pertussis, tetanus, rubella, measles, and BCG) administered 22–34 months post-transplant.	(Vlachos et al., 2001)
Severe chronic active Epstein-Barr virus	1	Complete remission without circulating EBV-DNA has continued for 15 months transplant.	(Ishimura et al., 2005)
Behcet's disease	1	Twenty-three months after CBT, the patient is doing well and has no signs or symptoms of Behcet's disease	(Tomonari et al., 2004)
Mucopolysaccharidosis type IIB (Hunter syndrome)	1	Two years after transplant approximately 55% normal plasma iduronate sulfatase. activity has been restored and abnormal urinary excretion of glycosaminoglycans has nearly completely resolved.	(Mullen et al., 2000)

Conclusion and future perspectives

Microenvironment of mammalian UC and the intrinsic properties of residing cells have to be considered as a valuable source of stem cells to be used in the future for both autologous and allogeneic transplantations. They can be harvested after birth with low cost, cryogenically stored, thawed, and efficiently expanded for therapeutic purposes. In many lineages tested so far, they seem to give promising results in regenerative therapeutic applications, especially in orthopedic and cartilaginous interventions. It was also shown by several experiments that UC-derived stromal cells are more efficient in terms of stem cell potency as compared with bone-marrow derived mesenchymal stem cells. Additionally, the shorter doubling time of cultured UC-derived stem cells compared with bone marrow mesenchymal stem cells (Suva et al., 2004) would give an easier and rapid propagation of these cells. Together with the distinct advantages of the UC, such as accessibility with little or no ethical concerns and painless procedures to donors with lower risk of viral contamination, it is generally accepted that the UC should be considered as an alternative to bone marrow. The ability to introduce exogenous DNA into the perivascular cells of UC stroma (Baksh et al., 2007) makes them potent stem cells for gene therapies (Hamada et al., 2005). Most recently, interferon- expressing UC stromal cells were targeted to experimentally developed lung tumors by intravenous and subcutaneous injections and were found to significantly reduce the tumor burden (Rachakatla et al., 2007), which indicated the usability of UC stromal cells in cancer gene therapy.

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First Published September 2010

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