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Thursday, 25 August 2016 00:00

Stem Cells – What, Why, Whereabouts and When? – PART III

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Pierre Schembri-Wismayer MD PhD MMCPath.
Lecturer
Department of Anatomy & Cell Biology, Faculty of Medicine,
University of Malta

Ethical and Safety issues


I will not be discussing the ethical issues with embryonic stem cells and personhood in detail here. However other ethical issues relating to stem cell therapy should be noted.

A possible cause for concern with stem cell therapy involves the risk of cancer [18]. Whilst this was hardly considered till a few years ago, nowadays, the literature teems with papers about tumour stem cells.

Mouse experiments involving the injection of stem cells or their progenitors clearly show the link with teratomas [19].

In the case of  embryonic stem cells, prolonged  in vitro culture can  be associated with genetic changes making embryonal stem cells similar to embryonal carcinomas [20]. This raises important questions about safely using embryonic stem cell lines propagated for a long time in vitro as a source of donor stem cells.

Although the amount of therapeutic studies using embryonic stem cells is presently very small, and no such statistics can be calculated, there is theoretically an increased risk of cancer developing in stem cells.

The increased plasticity of adult stem cells and the possibility of creating  patient-specific stem cells through processes similar to therapeutic cloning may make this a mute point in the near future.

Regarding tumour stem cells, the author’s personal opinion is that tumour cells, upon becoming immortal obtain much of the properties of stem-ness. However,  many papers now specifically describe  a specific sub-population of tumour stem cells[21, 22]. Whichever of these positions is the more accurate, there is little doubt that the more primitive a cell, the more propensity it has for malignant transformation. Due to this, detailed and extensive studies following transplantation of stem cells (autologous or heterologous) will be required before the procedure will be accepted as one with minimal associated risk.

Stem cell collection and banking

With all this stem cell-related research ongoing throughout the world, are there any measures worth taking up locally?

In the author’s opinion, the obvious and relatively easy option is to start up public cord blood banking. In fact a proposal document had been submitted to the health authorities by the author on behalf of a private charity a number of years ago.

Cord blood banking has been developed over the last decade or so in a number of countries around the world, including Italy, the Netherlands and the UK. Recognition of the usefulness of this resource were heralded by titles such as “turning garbage into clinical gold” in some of the world’s most prestigious scientific journals [23].

Cord blood banking can be separated into private and public banking. Private/individual banking normally  involves the preservation of the cord blood from a child’s placenta at birth and keeping those blood cells  for the child in question. This involves an initial payment and sometimes a recurrent payment to cover cryopreservation. Since the blood is only tested for infective organisms and does not need to be cross-matched against other individuals, it is relatively cheap to bank such blood.

In 1999, the American pediatric association issued a recommendation stating “Families may be vulnerable to emotional marketing at the time of birth of a child and may look to their physicians for advice. No accurate estimates exist of the likelihood of children to need their own stored cells. The range of available estimates is from 1:1000 to 1:200 000. Empirical evidence that children will need their own cord blood for future use is lacking. There also is no evidence of the safety or effectiveness of autologous cord blood transplantation for the treatment of malignant neoplasms. For these reasons, it is difficult to recommend that parents store their children's cord blood for future use”[24].

This was before the recognition of the different types of stem cells found in cord blood and their much greater plasticity potential. However even much more recently, the Canadian Society of Obstetricians and Gynaecologists issued the following amongst a long list of recommendations “5. Altruistic donation of cord blood for public banking and subsequent allogeneic transplantation should be encouraged when umbilical cord blood banking is being considered by childbearing women, prenatal care providers, and(or) obstetric facilities. 6. Collection and long-term storage of umbilical cord blood for autologous donation is not recommended because of the limited indications and lack of scientific evidence to support the practice. [25].

Public banking is much more expensive on a per unit basis but provides a resource for the whole health service. Due to the relative immunological naivety of cord blood, a perfect 6/6 major HLA match is not required for successful transplantation. 4/6 matches are often successful.

Studies by the Turin cord blood bank have in fact found that with just 500 units (1/10th of the amount of cord units which could be collected in a year in Malta) would be able to successfully cross match about 90% of the Italian population, ie more than 50 million people[26].

Until recently, cord blood was only found adequate for transplant into children and small adults of less than 50kg body mass, due to a need for more stem cells to adequately replace bone marrow in a larger individual[27].

Recent studies  however are suggesting a wider range of potential recipients due to a number of modifications including the simultaneous transfusion of more than one cord blood unit into the same patient [28] as well as ex-vivo expansion of the stem cell population [11, 29].

So Cord blood banking might just be the most useful stem cell-related health investment for the local health authorities. Private public partnerships may also provide a useful option, especially to allay costs.  Here, public health authorities  could take over cord blood units banked privately  for individuals after a fixed time period or after private individuals decide to stop paying cryopreservation costs, thus forfeiting ownership. By performing HLA typing and by recording these units in a database, they will slowly build up a local stem cell therapeutic resource, with the private sector having initially footed the start-up cost.


References


1. Civin CI. Cloned Photomicrographs, Not Cloned Cells. Stem Cells 2005. Available from: http://stemcells.alphamedpress.org/cgi/reprint/2005-0656v1.pdf

2. Ao A, Ray P, Harper J, Lesko J et al., Clinical experience with preimplantation genetic diagnosis of cystic fibrosis (delta F508). Prenat Diagn 1996; 16(2): 137-42.  

3. Itskovitz-Eldor J, Schuldiner M, Karsenti D et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med 2000; 6(2):88-95.

4. Nichols J, Evans EP, Smith AG. Establishment of germ-line-competent embryonic stem (ES) cells using differentiation inhibiting activity. Development 1990; 110(4):1341-8.

5. Sayles M, Jain M, Barker RA. The cellular repair of the brain in Parkinson's disease--past, present and future. Transpl Immunol 2004; 12(3-4):321-42.  

6. Rao MS. Stem sense: a proposal for the classification of stem cells. Stem Cells  2004; 13(5):452-5.

7. Minguell JJ, Erices A, Conget P. Mesenchymal stem cells. Exp Biol Med  2001; 226(6):507-20.

8. Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther 2003; 5(1):32-45.

9. Cannon J, Haas M. The Human Cloning Prohibition Act: did Congress go too far? Harvard J Legis 1998; 35(2):637-45.

10. Jasudowicz T. [Human cloning from the perspective of The Council of Europe bioethical standards]. Med Wieku Rozwoj 2001; 5(1 Suppl 1):213-25.

11. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385(6619):810-3.

12. Perry AC, Wakayama T. Untimely ends and new beginnings in mouse cloning. Nat Genet 2002; 30(3):243-4.

13. Stojkovic M, Lako M, Stojkovic P et al. Derivation of human embryonic stem cells from day-8 blastocysts recovered after three-step in vitro culture. Stem Cells 2004; 22(5):790-7.

14. Archundia A, Aceves JL, Lopez-Hernandez M et al. Direct cardiac injection of G-CSF mobilized bone-marrow stem-cells improves ventricular function in old myocardial infarction. Life Sci 2005; 78(3):279-83.  

15. Kuo CK, Li WJ, Mauck RL, Tuan RS. Cartilage tissue engineering: its potential and uses. Curr Opin Rheumatol 2006; 18(1):64-73.

16. Stainier D. No stem cell is an islet (yet). N Engl J Med 2006; 354(5):521-3.

17. Aoki H, Hara A, Nakagawa S et al. Embryonic stem cells that differentiate into RPE cell precursors in vitro develop into RPE cell monolayers in vivo. Exp Eye Res 2006; 82(2):265-74.

18. Filip S, Mokry J, English D. Stem cell plasticity and carcinogenesis. Neoplasma 2006; 53(2):87-91.

19. Stevens LC. Teratocarcinogenesis and spontaneous parthenogenesis in mice. Results Probl Cell Differ 1980; 11:265-74.

20. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 2005; 33(Pt 6):1526-30.

21. Fang D, Nguyen TK, Leishear K. et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 2005; 65(20):9328-37.

22. Sperr WR, Hauswirth AW, Florian S, Ohler L, Geissler K, Valent P. Human leukaemic stem cells: a novel target of therapy. Eur J Clin Invest 2004; 34 Suppl 2:31-40.

23. Thompson C. Umbilical cords: turning garbage into clinical gold. Science 1995; 268(5212):805-6.

24. Cord blood banking for potential future transplantation: subject review. American Academy of Pediatrics. Work Group on Cord Blood Banking. Pediatrics 1999; 104(1 Pt 1):116-8.

25. Armson BA. Umbilical cord blood banking: implications for perinatal care providers. J Obstet Gynaecol Can 2005; 27(3):263-90.

26. Rendine S, Curtoni ES, di Celle PF et al. Analysis of the turin umbilical cord blood bank registry. Transfusion 2000; 40(7):813-6.

27. Narimatsu H, Kami M, Miyakoshi S et al. Graft failure following reduced-intensity cord blood transplantation for adult patients. Br J Haematol 2006; 132(1):36-41.

28. Wiktor-Jedrzejczyk W, Rokicka M, Urbanowska E et al., Simultaneous transplantation of two allogeneic units of cord blood in an adult patient with acute myeloblastic leukemia: a case report. Arch Immunol Ther Exp (Warsz) 2005; 53(4):364-8.

29. Robinson SN, Ng J, Niu T et al., Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 37(4):359-66.

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