UMBILICAL CORD BLOOD BANKING (UCBB)

Allogenic and autologous hematopoietic stem cell transplantations are used in treatments of hematological and metabolic diseases. The main challenges of allogenic bone marrow transplantations are to find right elective HLA donor, HLA incompatibility and to have GvHD. Although number of volunteer bone marrow donor has reached 9 million worldwide, some patients cannot get transplantation due to HLA incompatibility. Cord blood has been thrown away with umbilical cord and placenta at birth until quite recently. It contains rich hematopoietic and non-hematopoietic stem cell sources and become important for treating hematological diseases and use in regeneration medicine application as an alternative resource.


History

Fetal liver cells have become a promising resource for stem cell transplantation after revealing their properties about hematopoietic activities and low immune reactions in 1970s. However, due to low success rate and improvement of allogenic bone marrow transplantation, use of fetal liver cells in multiple hematological disease treatments has been abandoned.

Chernobyl Disaster in 1980s has sparked a debate about alternative stem cell resources (fetal and neonatal cells) for radiation accident recovery. E. A. Bosy and H.E. Broxymayer asserted that umbilical cord blood collected at birth might contain enough hematopoietic stem cell/hematopoietic progenitor cell for therapy. This view has strengthened when it is understood that it is possible to do cell culture of cord blood derived hematopoietic progenitor cell in long periods. This hypothetical studies transform into an international cooperation over time and conduce to the first successful cord blood transplantation to treat engraftment and hematological disease.

First of all, Dr. Dougles and his colleagues determined that there is required minimum number of progenitor cells in cord blood (unless erythrocytes have been purged) for successful engraftment and there was any cell loss after one time freeze-thawing. Then, first cord blood was transplanted into Fanconi anemia patient by Gluckman and his colleagues on 6 October 1988. Required transplant cord blood obtained from HLA matched sibling. Patient did not develop GvHD and long term hematological and immunological structure is ensured.

After this first clinical experience, it is shown that cord blood transplantation is occur after myeloablative application by HLA matched and HLA mismatched Cord Blood transplantations.

Cord blood has transplanted worldwide in thousands of cases ever since. Autologous, relative and non-relative cord bloods are used to heal multiple malign and non-malign hematological diseases.


Umbilical Cord Blood Banking (UCBB)

Cord blood banks aim to provide cord blood derived hematopoietic stem cells for autologous, relative and non-relative transplantations and today over 250000 samples have been stored in more than 100 institutions worldwide.

First cord blood banking studies were started by Dr. Hal Broxmeyer at Indiana University School of Medicine. First 7 successful allogenic transplantation out of 10 cord blood samples which had been stored by Dr. Broxmeyer, led to open allogenic cord blood banks. First established allogenic cord blood banks in 1993 are New York Blood Center (New York, USA), Milan Cord Blood Bank (Milan, Italy) and Bone Marrow Donor Center (Dusseldorf, Germany). Public allogenic cord blood banking models triggered to found family cord blood banks where store hematopoietic stem cells for future autologous and relative based use.


Umbilical Cord Blood Banking (UCBB) in Turkey

Ministry of Health Cord Blood Banking Regulation released at 05.07.2007 consists of procedure and principles about foundations, activities and auditing of cord blood banks.

National Cord Blood Coordination Board was constituted in order to set national standards and strategies and improve cord blood banking in Turkey in the light of European developments.

Also, Physical and technological obligations that cord blood banks must have was stated. Accordingly, Cord blood banks in Turkey must provide cellular process units and suitable storage conditions which are in the “Good Manufacturing Practices-GMP” standards defined at Eudralex volume 4, supplements 1.

UCBB encourages hybrid cord blood banking in Turkey. Hybrid CBB carries out cord blood banking for family and public welfare.

CBB Regulation set deterrent provision and control instructions against to send samples abroad for storage and false statements and advertisements that worry families.

For now, only University hospitals and private health services continue doing Cord Blood Banking in Turkey.


Cord Blood Stem Cells

Cord blood is a great resource in terms of high amount and type of stem cells. Cord blood contains hematopoietic stem and progenitor cells, mesenchymal stem cells and endothelial progenitor cells.


Cord Blood Derived Hematopoietic Stem and Progenitor Cells

The ratio of cord blood derived CD34high+, CD38low/neg hematopoietic stem cells which regenerate bone marrow long term in SCID mice is 600 cell/c. This ratio is higher than adult bone marrow and cytokine-induced peripheral blood. Frequency of cord blood-derived hematopoietic progenitor cells (CFU-GM, BFU-E, CFU_GEMM) and their proliferation capacities is higher than bone marrow, too. Therefore, 50-200 ml of cord blood sample can be used for successful transplantation instead of using high amount of bone marrow (This amount can be decreased condensedly by using cell separation method).

Recently, clinical researchers have been focus on transplantation of two different cord blood sample at same time in order to expand cell numbers that provided from single cord blood samples. Barker and his friends transplanted dual partially matched HLA cord blood into hematological patients in 2005. It has achieved low GvHD, high engraftment and transplant-based mortality in these patients. Nevertheless, it is necessary to focus on use of two different cord blood samples in adults for now.

Another method that increases transplant cells in numbers is reproduction of hematopoietic stem cells in vitro, in other words ex vivo expansion. In a research that studies SCF, G-CSF and megakaryocyte growth and differentiation factors by McNicce and colleagues, cord blood derived hematopoietic stem cells has been reproduced and fast but short term engraftment has been achieved in fetal lamb. Not being able to ensure long term engraftment was engaged to not being able to proliferate hematopoietic stem cells in real. In another study, hematopoietic stem cells produced in stroma non-contact system were transplanted into primary, secondary and tertiary patients consecutively by Lewis ID and his colleagues. In conclusion, today expansion of cord blood in ex vivo for clinical practice is still an unclarified phenomenon.


Cord Blood Derived Mesenchymal Stem Cells

Mesenchymal stem cells are rare and multipotent cell types which support hematopoiesis and form to osteocytes, adipocytes and chondrocytes. These properties make mesenchymal stem cells irreplaceable devices for future cell based therapies. For now, Bone marrow is the main source of isolation of mesenchymal stem cells. However, it is showed that they can be isolated from adipose (fat) tissue and controversial cord blood.

Fibroblast-like cells in cord blood which adherence to surface of culture flask generates mesenchymal stem cell groups. They also differ in expression of CD90, CD105 and CD106 in addition to have same classic mesenchymal stem cell markers like other tissue-derived mesenchymal stem cells. These cells have difficulties in adipogenic manipulation due to their ontogenic age when compared to bone marrow and adipose derived mesenchymal stem cells in terms of differentiation capacity. Besides, cord blood derived stem cells have more proliferation potential that bone marrow and adipose derived stem cells.

The important role of mesenchymal stem cells in microenvironment of bone marrow and their abilities of hematopoiesis support bring into question of their use next to bone marrow.

It is assumed that after transplantation, mesenchymal stem cells will be able to secrete hematopoietic cytokines and contribute to build microenvironment of new bone marrow. Plus, mesenchymal stem cell transplantation is a suitable source for treatments of metabolic disease such as osteogenesis imperfecta and future gene therapies.


Cord Blood Derived Endothelial Progenitor Cells

Angiogenesis is formation of new blood vessels by endothelial cells in damaged, ischemic, and regenerated organs. Isolation of Endothelial progenitor cells from cord blood was performed by different study groups. Only 2% of CD34+ cells which are isolated from cord blood, have VEGRF-2. Cord blood derived CD34+ and VEGRF-2+ cell groups carry endothelial markers such as VE-cadherin and E-selectin. Endothelial cells differentiated from cord blood derived endothelial progenitor cells are more sensitive to angiogenic factors.


Cord Blood Immunity

Cord blood have different types of immune cells that decrease engraftment time and enable to have mild GvHD when compared to Bone marrow. Immature dendritic cells in cord blood cause T-cell anergia in vitro by stimulating T-regs. Besides, cord blood lymphocytes are naïve, immature and rich in double negative CD3+. Cord blood lymphocytes generates enough mRNAs for interferon-γ, IL-4 and IL-10 but less for IL-2. On the other hand, polyclonal T cell repertory can be protected from apoptosis because of its full-grown and low level of CD95 expression. NK function is reduced.

Acute GvHD occurs in early phase of allogenic bone marrow transplantation followed by cytokine secretion. Therefore, it is predictable that cord blood transplantation can cause weak GvHD than bone marrow which contains mature and active T cells.

It was thought that cord blood prevents GvL after transplantation due to comprising less and immature immune cells than Bone marrow. However, it was detected that after allogenic transplantation, T and NK cells in cord blood actives and cause GvL without major GvHD in experiments.


Use of Cord Blood in Tissue Regeneration

Damaged Liver Tissue Recovery

Hepatic round Cells are the original stem cells of liver tissue. Surprisingly, these cell types have similar markers as peripheral. Hematopoietic progenitor cells have such as CD34, CD90 and c-Kit. For this reason, it is thought that they have a potential to generate hepatocytes in cord blood derived cells.

Human cord blood intraperitoneal injection induced liver regeneration and decreased the death rate in NOD/SCID mice with chemically damaged liver.


Diabetes Type I

A research held by Ende N and his colleagues shows that Cord blood applied to autoimmune NOD mice which have diabetes type I, decreases glucose and insulin level of blood and increases life expectancy.


Central Nervous system diseases (Parkinson and Alzheimer’s disease)

Human cord Blood cells applied not as intravenous and without immune suppressor, extent the time of Parkinson’s onset in mouse models associated with Parkinson by Ende N and his colleagues. Same group also slow down the development of amyloid plaque in mice with Alzheimer’s Disease.


Stroke

In stroke modeling in SCID mice, middle cerebral artery has been completely blocked and CD34 cells selected from cord blood has been injected as intravenous after 48 hours. Neovascularization and endogenous neurogenesis has been started in damaged area after application.


Conclusion

Results show that allogenic, autologous and relative cord blood transplantation has been successful in treatments of malign and non-malign hematological and metabolic diseases in children. It gives similar results in adult patients as well.

Non-hematopoietic stem cell groups which are possible to isolate from Umbilical cord blood, are the most practical and compatible devices in tissue and organ regeneration.



Resources:

  1. E Gluckman and V Rocha, History of the clinical use of umbilical cord blood hematopoietic cells, Cytotherapy (2005) Vol:7 :219-227
  2. HE Broxymeyer, Biology of cord blood cells and future prospects for enhanced clinical benefit, Cytotherapy (2005) Vol:7 : 209-218
  3. M. Körbling, S. Robinson, Z. Estrov, R Champlin, and E Shpall, Umbilical cord blood drives cells for tissue repair, Cytotherapy (2005) Vol:7 : 258-261
  4. Susanne Kern, Hermann Eichler, Johannes Stoeve, Harald Klüter, Comparative Analysisi of Mesenchymal Stem Cells from Bone Marrow, Umbilical
  5. Cord Blood or Adipose Tissue, Stem Cells Express,2006
  6. Ömer N. Koç, Mezenşimal Kök Hücreleri: Hematolog Perspektifi, XXX. Ulusal Hematoloji Kongresi, Mezuniyet Sonrası Eğitim Kursu Kitapçığı
  7. Dr.Mehmet Ertem, Kök Hücre Tipleri: Kordon Kanı, THD Kök Hücre Kursu,2006

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Genkord Biotechnology and Health Services are founded as an umbilical cord blood bank in 2003.

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