Stem cells of umbilical cord blood banking

Transcription

1 Archives of Perinatal Medicine 21(2), 17-22, 2015 REVIEW PAPER Stem cells of umbilical cord blood banking MARTA KRUSZYŃSKA, GRZEGORZ KRUSZYŃSKI, GRZEGORZ H. BRĘBOROWICZ 1 Abstract Current understanding and outlook for umbilical cord blood (UCB) stem cells potential are very promising mainly due to their high ability to regenerate damaged tissue and self-renewal. On the other hand, easy access to their acquisition contributed nowadays to the more and more worldwide popular storage of UCB in either private or public banks of stem cells. However commercial aspect of UCB banking remains controversial. Not only concerns the cost benefits ratio related to the storage but also for ethical and legislative reasons. Considering storage related issues it s worth to become familiar with the current possibilities of application and ongoing latest research, designed to expand UCB use in regenerative medicine. Ethical aspect as well as relative advantages in the context of a significant economic burden associated with expensive procedure necessary to isolate and preserving UCB even for years, is also relevant. Official stance and recommendations of American Society for Blood and Marrow Transplantation or even Polish Gynecological Society concerning collection and storage of UCB are important to every practitioner. They should get confronted with the level of knowledge about cord blood banking of individuals determined to donate umbilical cord blood for stem cells bank. Key words: blood banking, umbilical cord, stem cells Umbilical cord blood transplantation Increased interest of umbilical cord banking (UCB) occurred in 1980, when Leary, Broxmeyer and Gluckman demonstrated that UCB could be used as a source of hematopoietic cells in clinical setting [1]. Later in 1988 Broxmeyer proved that UBC is a rich source of transplantable hematopoietic stem cells (hematopoietic progenitor cells HPCs). The same year using such information Gluckman in France for the first time documented transplantation of HPCs from UCB, instead of bone marrow (BM). The patient was a 5-year-old boy with Fanconi anaemia. UCB derived from sister with identical histocompatibility antigen HLA (Human Leukocyte Antigen) was used to restore the haemolymphopoietic system [2]. After a successful transplantation any serious complications had not developed. The patient had not experienced graft-versus-host disease (GvHD), and now after 26 years still enjoys good health. It has been concluded as a huge success and a breakthrough in transplantation medicine [3]. Since the first umbilical cord blood transplantation (UCBT) there has been tremendous progress in procurement technology, blood banking and especially its use. A certain advantage characterize stem cells derived from umbilical cord blood (CB). It is much more acceptable level of non-compliance within HLA compared with the bone marrow cells. In addition, their CB content is ten times higher than in bone marrow, they are less mature and have a greater proliferation potential [4, 5]. In the most developed countries like the USA or Japan, UCBT represents about 50% of all transplantations performed [6]. Such transplants are characterized by a lower morbidity risk and GvHD response. Another additional UCBT benefits feature low complications risk, painless and relatively lower cost collection comparing to bone marrow. Currently, umbilical cord blood treatment is applied in more than seventy cancerous and noncancerous diseases, while this number is constantly growing [7]. The cord blood contains different types of cells, including hematopoietic progenitor cells (HPCs) and mesenchymal stem cells (Mesenchymal Cells MCs). Currently HPCs are successfully applied in transplantation medicine. They are typically used to restore the hematopoietic and immune system. On the other hand, currently conducted researches on MCs offer hope to their widespread use in regenerative medicine. Among others, in diseases such as diabetes, Alzheimer's disease, ischemic heart disease, cerebral palsy, or spinal cord injury. However, it should be emphasized that there are only experimental methods of treatment rather than standard procedures [8-12]. 1 Department of Perinatology and Gynecology, Poznań University of Medical Sciences

2 18 M. Kruszyńska, G. Kruszyński, G.H. Bręborowicz Table 1. Comparison of stem cell sources Newborn Adult Embryonic Ability to differentiate into various cell types T T T High proliferation capacity T T Low risk of tumor formation T T Low risk of viral contamination T T Capacity for autologous transplantation T T Established/proven treatment in human patients T T Table 2. Diseases that could be treated with umbilical cord blood stem cells Acute leukemia Chronic leukemia Myelodysplastic syndrome Proliferative malignancies of the lymphatic system Plasmatic cells abnormalities Stem cell defect diseases Inherited red blood cells abnormalities Hereditary disorders of the immune system Bifenotypic (BAL) Lymphoblastic (ALL) Myelogenous (AML) Minimally differentiated Myelogenous (CML) Myelomonocytic (CMML) Lymphocytic (CLL) Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts (RARS) Refractory Anemia with Excess Blasts (RAEB) Refractory Anemia with Excess Blasts in Transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML) Prolymphocytic leukemia non-hodgkin lymphoma (NHL) Hodgkin's lymphoma (HL) Plasmacytoma Waldenström's macroglobulinemia Multiple myeloma Severe aplastic anemia (SAA) Paroxysmal nocturnal hemoglobinuria (PNH) Fanconi anemia Erythroblastopenia Beta-Thalassemia Sickle cell anemia Ataxia telangiectasia Severe Combined Immunodeficiency (SCID) SCID to non-functional T-helper cells Adenosine deaminase deficiency SCID Leukocyte adhesion deficiency X-linked severe combined immunodeficiency Platelets abnormalities Phagocytes diseases Other DiGeorge syndrome Kostmann syndrome Bare lymphocyte syndrome Omenn syndrome Wiskott-Aldrich syndrome Common variable Immunodeficiency Congenital amegakaryocytic trombocytopenia (CAMT) Reticular dysgenesis Chronic granulomatous disease (CGD) Chediak-Higashi syndrome Retinoblastoma Neuroblastoma Table 3. Examples of diseases where UCB use might be applied new treatment approach Lysosomal storage disease Histiocytosis Cancer Neurological disorders Mucopolysaccharidosis Hereditary disorders Adrenoleukodystrophy Krabbe disease Gaucher disease Wolman disease Niemann-Pick disease Mucopolysaccharidoses Sandhoff disease Metachromatic leukodystrophy Hemophagocytoses X-type histiocytoses Breast cancer Renal cell carcinoma Ewing's sarcoma Cerebral palsy Multiple clerosis Hurler syndrome Morquio syndrome Sanfilippo syndrome Sheie syndrome Hunter syndrome Gunther disease Cartilage hypoplasia Osteoporosis Lescha-Nyhana Syndrome Glanzmann thrombasthenia

3 Stem cells of umbilical cord blood banking 19 Table 4. New hope clinical trials and potential therapies Disease Ischemic heart disease Cerebral palsy Global development delay Alzheimer diseasee Autism Celebral palsy Skin diseases Spinal cord injury Osteoporosis Liver failure caused by HBV Neonatal hypoxic-ischemic encephalopathy Orthopedic cartilage repair Hypoplastic left heart syndrome Diabetes mellitus type 1 Diabetes mellitus type 2 Cell origin Umbilical cord banking Large interest about UCBT is contributed to the establishment of the first public stem cell bank by Pablo Rubinstein in New York as soon as in 1991 [13]. Currently there are about 160 publicly funded banks of stem cells around the world [14]. Their goal is to acquire, process and store UCB units for any patient who will need it. Therefore, blood gets to an international registry of bone marrow donors, and its main purpose are allogenic transplantations, mainly for patients unrelated to the donor. Samples positioned in the registry must be tested for genetics, infectious and neoplastic diseases. UCB must meet the requirements concerning volume and the number of stem cells. These standards are very restrictive and closely regulated. Donation of blood, which does not comply mentioned standards is rejected or transferred for research projects. In fact, 30 to 70% UCB units after a thorough interview and testing cannot be placed in the register [15,16]. UCB quality is extremely important because it can influence graft acceptance, or increase the risk of complications. Standards and guidelines for UCB storage are regulated by the Food and Drug Administration (FDA), the American Association of Blood Banks (AABB) and The Joint Accreditation Committee (JACIE). These standards apply to all aspects of umbilical cord blood banking enterprises [17]. Public Banks model guarantees the highest quality graft material, greatly facilitates the selection of the appropriate unit for a patient who needs a transplant. Contemporary, public banks store around units of UCB, yet demands continue to grow. Table 5. UCB banking standards concerns (according to FDA) A process for approval of vendors providing supplies The consenting, donor screening and collection process Product qualification, testing, processing, storage and release Equipment and facility maintenance A process for personnel selection and training A process to monitor and improve quality of services To meet the growing interest and due to the emerging market since 1992 so-called private cord blood banks started to appear. Private banks offer storage of UCB in order to use it in the future for the child itself (an autologous transplant) or for related family member (an allogeneic graft). Private CB banks often encourage parents to treat UCB as a kind of an insurance policy for a child. UCB application is widely extended, not only in transplantation, but also in regenerative medicine and immunology to increase its offer attractiveness. Although proofs that the UCBT will be useful in these possible applications remain uncertain [18]. Nowadays there are over 200 commercial banks and with at least 200 marketing branches. This is obviously a business model in which parents bear the costs associated with the collection, testing and storage of UCB. Banks providing these services derive profits from each unit of UCB stored, sometimes even for 25 years. Blood is not added to the international register of bone marrow donors because it is privately owned and can only be disposed by parents. Up to date commercial blood banks store about 4.0 million units of UCB. This amount might result from the fact that usually all collected units of cord blood are accepted for storage. They do not exert such strict criteria as public banks. Unfortunately, UCB attributes preserved by private banks are often lower than in public one, mainly due to the lack of mandatory guidelines concerning quality standards [18-20]. Interestingly, only five private UCB banks in Europe has been accredited by AABB, which guarantees the possibility of transplantation of donated material [11]. Increasingly, to allow autologous and allogeneic UCBT, solutions binding private and public donation are

4 20 M. Kruszyńska, G. Kruszyński, G.H. Bręborowicz made. Such a model of blood banking is already available in some countries in Europe, Asia and the Middle East. A kind of integrated banking system could increase to a standardized level quality of the stored UCB units and expand public register of donors, while reducing national health care system costs associated with the storage of CB. Considering private cord blood banking, attention must be paid to the actual amount of UCB units used for transplantation. According to the reports provided by private UCB banks in 2013, only 1015 UCB units were used, of which 530 were used for autologous and 485 for allogeneic transplants. Merely 59 banks provided the report. The most common use of autologous grafts (82%), in which private bank UCB was used were brain injuries such as ischemic encephalopathy, periventricular leukomalacia and cerebral palsy. 9% of autologous transplantations were exploited for the treatment of aplastic anemia, neuroblastoma and medulloblastoma. Approximately 7% was applied to clinical trials in patients with diabetes. It is worth noting that some of the autologous grafts were used in the treatment of leukemia, which is not recommended due to the risks of cancerous cells contamination. According to the study significant differences in the quality of UCB units derived from private banks were noted. It is important to draw more attention for better regulation and standardization of UCB units stored in private banks, thus their use in clinical conditions could be more effective [15]. grafts made with the use of UCB stored in private banks were in 37% applied for the treatment of blood, immune system, and bone marrow cancers. 39% UCBT were used in cases of hemoglobinopathies, where 28% concerned thalassemia and 11% sickle cell anemia. Another 19% of transplantations were for so-called rare diagnoses like Fanconi anemia, metabolic diseases, severe immunodeficiency, chronic granulomatous disease and other. Public banks as for the end of 2013 used UCB units, which is 30 times more than private, whereas the amount of blood stored in them was six times smaller (4 million compared to 0.7 million) [21]. Of course, private UCB banks can be a significant and important therapeutic source for families in some rare circumstances. These are usually siblings cancer and genetic diseases such as leukemia, sickle cell anemia, thalassemia, congenital marrow failure, immune deficiency, hereditary metabolic diseases (Table 6). Although it should be stressed that the probability of a perfect genetic match between siblings oscillate about 25-30%. Therefore siblings may require a bone marrow or UCB transplant from unrelated donor. It is also reasonable that if a child develop a cancer or other genetically determined condition, deposited UCB cannot be used for treatment, since it has the same genetic defects that caused illness [22]. Table 6. Indications for familial UBC collection Siblings disease Leukemia Immune deficiency Lymphoma Aplastic anemia Sickle cell anemia Thalassemia Eagerly presented by a private banks applicability of UCB in regenerative medicine should be treated as speculation, until clinical evidence for the benefits of their use is established. Still it is not clearly known whether the UCB, in contrast to stem cells derived from other sources, will be more useful in these optional applications, so deposition of CB as biological insurance is unwarranted. Access to the deposit UCB differs in particular countries. Public donation is still impossible or very limited in most regions. Thus many parents do not have a choice between public or private deposit. To choose private banking or rather abandon remains as the only option. There are also serious ethical aspects in case of indications to the family UBCT in countries where due to financial reasons only private storage of UCB is available. At the same time it should be highlighted that some private banks offer free banking for families whose older child requires treatment with the use of UCBT such as the mentioned hemoglobinopathies [23-25]. The American Society for Blood and Marrow Transplantation, the American Academy of Pediatrics (AAP), the American Medical Association (AMA) and the American Association of Obstetricians and Gynecology (AAOG) issued an official committee opinions on UCB to help parents decide which of the banks use to deposit cord blood. Principally they do not recommend blood storing as biological insurance against future disease or if there is no medical familial indications. Future plans for autologous UCB use in regenerative medicine are now considered insufficiently to recommend private blood banking.

5 Stem cells of umbilical cord blood banking 21 Table 7. Advantages and disadvantages of private and public cord blood banking Private banking Banking motivation Health insurance for the baby and first-degree relatives Save any patient in need Cost to banking Parent Free Suitable for unrelated patients No Yes Cord blood storage All samples are kept (for parents request) Public banking Only samples big enough for regenerative therapy are kept (over 30-70% collections are discarded) Estimated cord blood transplants to date Collection area National Selected hospitals that are often local to the bank The benefits seems to be too remote to justify significant costs of private storing. The probability of the autologous UCB transplant remains very low and is < 1/1500. Instead recommendations are to consider UCB donation for public banks if it is possible, in order to increase the chances of matching for patients who need a transplant [26]. Summary The number of UCB banks and the quantity of UCBT has significantly increased over the past 25 years. As well as technology used in both autologous and allogeneic transplants greatly developed. Today pregnant women have many options of CB storage although it should be emphasized that in various countries it is differently regulated. After childbirth umbilical cord blood is an easily accessible source of stem cells that have the ability to transform and self-renewal. Acquiring them is painless and not harmful. Therefore UCB collection storage gives a chance to preserve potentially life-saving cells that would normally be wasted and disposed after birth. Currently they are used mainly for blood cancers and immunological deficiencies therapies. Although believed that they will be useful to treat a variety of other diseases, up to date it seems still to be a speculation. It is worth to note that, unless there is such a possibility, public banking significantly increases the chances of UCB use. Storage of blood in commercial banks, to use for autologous transplants yet is not recommended. The information concerning the advantages and disadvantages of public and private UCB banking should be made available to all parents in a precise and understandable manner. It will allow parents to make an expertise supported and conscious choice. References [1] Mayani H., Lansdorp P.M. (1998) Biology of human umbilical cord blood-derived hematopoietic stem/ progenitor cells. Stem Cells 16(3): [2] Gluckman E., Broxmeyer H.A., Auerbach A.D. et al. (1989) Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N. Engl. J. Med. 321(17): [3] Gluckman E., Ruggeri A., Rocha V. et al. (2011) Family-directed umbilical cord blood banking. Haematologica 96 (11): [4] Alkindi S., Dennison D. (2011) Umbilical Cord Blood Banking and Transplantation: A short review. Sultan Qaboos Univ. Med. J. 11(4): [5] Kim Y.J., Broxmeyer H.E. (2010) Immune regulatory cells in umbilical cord blood and their potential roles in transplantation tolerance. Crit. Rev. Oncol. Hematol. 79(2): [6] Alois Gratwohl, M.D., Marcelo C., Pasquini M.D. et al. (2015) One million haemopoietic stem-cell transplants: a retrospective observational study. The Lancet Haematology 2(3): [7] Roura S., Pujal J.M., Gálvez-Montón C. et al. (2015) The role and potential of umbilical cord blood in an era of new therapies: a review. Stem Cell Res. Ther. 2: [8] Prasad V.K., Mendizabal A., Parikh S.H. et al. (2008) Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composisiton of the graft on transplantation outcomes. Blood 112: [9] Roura S., Gálvez-Montón C., Bayes-Genis A. (2014) Umbilical cord blood-derived mesenchymal stem cells: new therapeutic weapons for idiopathic dilated cardiomyopathy? Int. J. Cardiol. 177(3): [10] Manca M.F., Zwart I., Beo J., Palasingham R. et al. (2008) Characterization of mesenchymal stromal cells derived from full-term umbilical cord blood. Cytotherapy 10(1): [11] [12] Rebulla P., Pupella S., Santodirocco M. et al. (2015) Multicentre standardisation of a clinical grade procedure for the preparation of allogeneic platelet concentrates from umbilical cord blood. Blood Transfus. 31: 1-7. [13] Rubinstein P, Dobrila L, Rosenfield R.E. et al. (1995) Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc. Natl. Acad. Sci. USA 92: [14]

6 22 M. Kruszyńska, G. Kruszyński, G.H. Bręborowicz [15] Ballen K.K., Verter F., Kurtzberg J. (2015) Umbilical cord blood donation: public or private? Bone Marrow Transplantation 50: [16] Anasetti C. (2015) Use of alternative donors for allogeneic stem cell transplantation. Hematology Am. Soc. Hematol. Educ. Program 1: [17] Armson B.A., Allan D.S., Casper R.F. (2015) Umbilical Cord Blood: Counselling, Collection, and Banking. J. Obstet. Gynaecol. Can. 37(9): [18] Matsumoto M.M., Matthews K.R. (2015) A Need for Renewed and Cohesive US Policy on Cord Blood Banking. Stem Cell Rev. 11(6): [19] Elmoazzen H., Holovati J.L. (2015) Cord blood clinical processing, cryopreservation, and storage. Methods Mol. Biol. 1257: [20] Sun J, Allison J, McLaughlin C. et al. (2010) Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion 50: [21] Ballen K.K., Gluckman E., Broxmeyer H.E. (2013) Umbilical cord blood transplantation: the first 25 years and beyond. Blood 122: [22] Kekre N., Antin J.H. (2014) Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist. Blood 124(3): [23] Mazini L., Matar N., Bouhya S. (2014) Umbilical Cord Blood Banking for Transplantation in Morocco: Problems and opportunities. J. Stem Cells Regen. Med. 10(2): [24] tee-opinions/committee-on-genetics/umbilical-cord- Blood-Banking [25] medical-ethics/code-medical-ethics/opinion2165.page [26] Ballen K.K., Barker J.N., Stewart S. (2008) ASBMT Committee Report: collection and preservation of cord blood for personal use. Biol. Blood Marrow Transplant. 14: J Marta Kruszyńska Department of Perinatology and Gynecology Poznań University of Medical Sciences Poznań, Polna 33, Poland m-kruszynska@wp.pl