Introduction:

Stem cells are the primordial or original cells that give rise to life and being of a living thing, from animals and humans. Zygote formed from the fusion of sperm and oocyte is the first line of stem cell that is “totipotent” meaning it gives rise to embryonic stem cells and from there to epiblast and embryonic germ stem cells, that are all “pluripotent” meaning they form all the differentiated cell types of a given tissue. These pluripotent stem cells lineage give rise to the primordial germ cells that form all the tissues from skin to bone marrow and all other body tissues. The aim of stem cell therapy over the past half a century has been to induce pluripotent stem cells (IPS) in different body tissues to repair or replace the damaged tissues and cells of specific organ or parts of the body in vitro (in lab) and in vivo (in live beings) (1-2).

 Bone marrow transplant has been the earliest stem cell therapy in the treatment of leukemia and lymphoma and has been widely clinically practiced over almost half of a century all over the world with quite success. Later on umbilical cord blood storage and use for transplants has been clinically practiced, while other forms of stem cell therapy such as the use of induced pluripotent stem cells (IPS) for a wider treatment of cancers and autoimmune disorders of different organs and tissues have been mostly experimental. Another common clinical use of bone marrow transplants has been in chemotherapy of cancers, to introduce the hematopietic stem cells within the bone marrow to replace the destroyed healthy cells by chemotherapy. The most common side-effects of bone marrow and other transplants traditionally has been graft vs. host reaction that rejects the transplant. Another stem cell therapy, “Prochymal” based on allogenic stem cells therapy using mesenchyme stem cells has been used recently in the management of such transplant rejections (3-4).

 While in the past it was thought that the stem cells are basically in bone marrow and umbilical cords and most organs and tissues unlike the epidermis of the skin do not possess the capacity of renewal, in recent years it has become apparent that some other tissues in fact contain stem cells for potential renewal (5). One main reason of the delay in the stem cells therapy has been lack of recognition of different stem cells across different tissues with different potential capacities unlike the progenitor bone marrow and umbilical cord stem cells. As explained above while many of these stem cells are pluripotent, most are multipotent or unipotent, meaning having the capacity of their own specific tissue cells regeneration (6-7). In fact and with a comprehensive perspective, cancer cells could be considered as stem cells for their capacity of turnover and proliferation. This fact has been known and discussed as early as late 80s, but only recently has received widespread attention and acceptance. The cancer stem cell concept is important for opening a new venue to the novel approaches in anti-cancer therapies that instead of killing all or partial cancer cells with the potential of regrowth, to target the cancer stem cells for final cure with no possibility of relapse (8-9).

 The advancement in stem cell research over years has led to the distraction and culture of progenitor or totipotent stem cells in vitro first from the animal models such as mouse, and now from the human’s blastocysts, with the ability of generation all the differentiated cells of a being such as human, hence “cloning” that puts the science in the jeopardy of Frankenstein as it has long been anticipated and infuriated (10-11). Other than blastocysts, the progenitor or embryonic stem cells with capacity of generating differentiated tissues of the whole being, it has been shown that epiblasts first from mouse and now humans could created such pluripotency (12-14). Moreover and morally riskier is the capability of adult stem cells to be reprogrammed to a pluripotent state, through transferring the adult nucleus into an oocyte or by fusion with a pluripotent cell. The most famous example of this cloning has the creation of “Dolly” the sheep by transferring of a somatic nucleus into an oocyte (15-18).

 From a therapeutic not creational standpoint, the ability of regenerating new cells in the damaged and destroyed tissues is the art and science of IPS (induced pluripotent stem cells). Despite knowing for long that some amphibians could naturally regenerate limbs, eye or other injured body parts, therapeutic regeneration or regrowth of damaged or destroyed tissues medically by IPS is quite recent (2, 19-20). Since the original retrovirus-mediated induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by some defined factors in 2006-2007 (21), rapid progress has been made to generate iPS cells from adult human cells (22), a range of tissues that can be reprogrammed (23), and from patients with specific diseases (24). The number of transcription factors required to generate iPS cells has also been reduced (25), and the efficiency of iPS cell generation has increased (26), and techniques have been devised without viral vectors integration (27).

 From Research to the bed side:

Haemopoietic stem cell transplantation by use of bone marrow, peripheral blood or cord blood is the oldest stem cell therapy widely in practice almost everywhere. While the patient’s own cells is used in such transplants commonly, the allogeneic stem cell transplantation by using donors’ cells are common as well in the treatment of haematological malignancies, such as leukaemia. Donor stem cells are also used to foster immune function of cancer patients following radiation and/or chemotherapy. Advances in immunology research has greatly increased the utility of bone marrow transplantation, through screening for the best match to prevent rejection and graft-versus-host disease (28-29). In contrast to the haemopoietic stem cell therapy that there is no need of cells culture or reconstitution of a multicellular tissue architecture prior to transplantation, these steps are needed in some other transplants, e.g. culture epidermis to provide autologous grafts for patients with third-degree burn wounds and limbal stem cells grafts for restoration of vision in patients suffering from chemical destruction of the cornea (30-31).

 Efforts to apply stem cell therapy in the treatment of neurodegenerative diseases has been ongoing since early 1990s, when human fetal dopamine cells were transplanted in Parkinson’s Disease (32). Since the fetal tissue as a transplant source was heavily unstable and problematic, neural stem cells as a potential optimal source of neural transplantation, not only in Parkinson’s but also in other neurodegenerative diseases such as Alzheimer’s and Huntington’s were studied and used (33-34). Clinical studies over the last 10 years suggest that stem cell transplantation also has potential as a therapy for neurodegenerative diseases. Clinical trials have involved grafting brain tissue from aborted fetuses, neural stem cells and multi-potent neural progenitor cells transplants into patients with Parkinson’s disease and Huntington’s disease (32-38). By the late 1990’s in one step ahead towards preventive interference with the process of neruodegenration, first protective gene delivery to the affected areas of brain through viral vectors was raised and studied (39). Since the viral delivery of neuro-protective factors held their own risk of the toxicity of the vectors, ex vivo gene transfer was designed to engineer cells to express the desired transgene in vitro, before transplantation for delivery of the gene product in vivo (40-41).  

There have also been some major achievements in the treatment of genetic and chromosomal disorders with stem cell therapy, including the successful treatment of children with X-linked severe combined immunodeficiency. However, the entire gene therapy field stalled when several of the children developed leukaemia as a result of integration of the therapeutic retroviral vector close to the LMO2 oncogene locus (42-43). Clinical trials have since restarted, and in an interesting example of combined gene/stem cell therapy, a patient with an epidermal blistering disorder received an autologous graft of cultured epidermis in which the defective gene had been corrected ex vivo (44). The stem cell therapy nowadays is interlinked with the other medical fields such as gene therapy bioengineering, and immunotherapy for optimal results. Stem cells undoubtedly offer tremendous potential to treat many human diseases and to repair tissue damage resulting from injury or ageing. The danger, of course, lies in the potentially lethal cocktail of desperate patients, enthusiastic scientists, ambitious clinicians and commercial pressures (45). Internationally agreed, and enforced, regulations are essential in order to protect patients from the dangers of stem cell tourism, whereby treatments that have not been approved in one country are freely available in another (46).

 Beyond stem cell therapy that indeed is repair of damaged tissues, an alternative strategy is to stimulate the patients’ endogenous stem cells to divide or differentiate, as happens naturally during skin wound healing. It has recently been shown that pancreatic exocrine cells in adult mice can be reprogrammed to become functional, insulin-producing beta cells by expression of transcription factors that regulate pancreatic development (47). A range of biomaterials are already in clinical use for tissue repair, in particular to repair defects in cartilage and bone(48). Advances in tissue engineering and materials science offer new opportunities to manipulate the stem niche and either facilitate expansion/differentiation of endogenous stem cells or deliver exogenous cells. Hydrogels that can undergo controlled sol–gel transitions could be used to release stem cells once they have integrated within the target tissue (1, 49)

Although most of the new clinical applications of stem cells have a long lead time, applications of stem cells in drug discovery are available immediately. Adult tissue stem cells, ES cells and iPS cells can all be used to screen for compounds that stimulate self-renewal or promote specific differentiation programs. Finding drugs that selectively target cancer stem cells offers the potential to develop cancer treatments that are not only more effective, but also cause less collateral damage to the patient’s normal tissues than drugs currently in use. In addition, patient-specific iPS cells provide a new tool to identify underlying disease mechanisms. Thus stem cell-based assays are already enhancing drug discovery efforts. Many toxic compounds (different chemical compounds, pharmaceutical drugs, other hazardous chemicals, or environmental conditions) which are encountered by humans and newly designed drugs may be evaluated for toxicity and effects by using iPSCs. Thus, the applications of iPSCs in regenerative medicine, disease modeling, and drug discovery are enormous and should be explored in a more comprehensive manner (1, 50).

 Dr. Mostafa Showraki, MD, FRCPC

Lecturer, School of Medicine, University of Toronto

Author: ADHD: Revisited Book

Adhdrevisited.com/medicinerevisited.com      

 Conclusion:

Stem cell therapy that started almost half a century ago with bone marrow transplant for the treatment of leukemia and lymphoma has advanced over years to the treatment of many more diseases from skin grafts to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and also rejunuvate vision of blind patients. Stem cell therapy has also advanced from in vitro to in vivo and also improved in transplants/grafts rejections through better screening of donors and new “Prochymal” stem cell therapies. The field has also advanced by interlinking with other related medical science fields such as gene therapy, immunotherapy and viral vectors delivery of protective factors such as neuro-protective factors in the treatment of neuro-degenerative diseases.

 References:

1. Watt FM, Driskell RR. (2010). The therapeutic potential of stem cells. Philos Trans R Soc Lond B Biol Sci. 365(1537):155-63.
2. Jaenisch R., Young R. (2008). Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567–582. 
3. Mahla RS (2016). Stem cells application in regenerative medicine and disease therapeutics. International Journal of Cell Biology. 7:1-24.
4. Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD, Porter DL, Uberti JP, King RJ, Confer DL (2008). Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program. Biology of Blood and Marrow Transplantation. 14(9 Suppl): 8–15. 
5. Zhao C., Deng W., Gage F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660. 
6. Watt F. M., Hogan B. L. (2000). Out of Eden: stem cells and their niches. Science 287, 1427–1430. 
7. Potten C. S., Loeffler M. (2008). Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001–1020.
8. McCulloch E. A., Minden M. D., Miyauchi J., Kelleher C. A., Wang C. (1988). Stem cell renewal and differentiation in acute myeloblastic leukaemia. Review. J. Cell Sci. Suppl. 10, 267–281. 
9. Clarke M. F., Dick J. E., Dirks P. B., Eaves C. J., Jamieson C. H., Jones D. L., Visvader J., Weissman I. L., Wahl G. M. (2006). Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344. 
10. Thomson J., Itskovitz-Eldor J., Shapiro S., Waknitz M., Swiergiel J., Marshall V., Jones J. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147. 
11. Andrews P., Matin M., Bahrami A., Damjanov I., Gokhale P., Draper J. (2005). Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem. Soc. Trans. 33, 1526–1530. 
12. Brons I. G., et al. (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195. 
13. Kerr C. L., Gearhart J. D., Elliott A. M., Donovan P. J. (2006). Embryonic germ cells: when germ cells become stem cells. Semin. Reprod. Med. 24, 304–313.
14. Tesar P. J., Chenoweth J. G., Brook F. A., Davies T. J., Evans E. P., Mack D. L., Gardner R. L., Mckay R. D. (2007). New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199. 
15. Gurdon J. B., Elsdale T. R., Fischberg M. (1958). Sexually mature individuals of Xenopus laevisfrom the transplantation of single somatic nuclei. Nature 182, 64–65.
16. Miller R. A., Ruddle F. H. (1976). Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell 9, 45–55.
17. Wilmut I., Schnieke A. E., McWhir J., Kind A. J., Campbell K. H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813. 
18. Gurdon J. B., Melton D. A. (2008). Nuclear reprogramming in cells. Review. Science 322, 1811–1815.
19. Anderson D. J., Gage F. H., Weissman I. L. (2001). Can stem cells cross lineage boundaries? Nat. Med. 7, 393–395.
20. Brockes J. P., Kumar A. (2005). Appendage regeneration in adult vertebrates and implications for regenerative medicine. Science 310, 1919–1922. 

1. Takahashi K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.
2. Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., Yamanaka S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131, 861–872. 

23. Aasen T., et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26, 1276–1284.
24. Dimos J. T., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221. 
25. Kim J. B., et al. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646–650. 
26. Wernig M., Meissner A., Foreman R., Brambrink T., Ku M., Hochedlinger K., Bernstein B. E., Jaenisch R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324. 
27. Stadtfeld M., Nagaya M., Utikal J., Weir G., Hochedlinger K. (2008). Induced pluripotent stem cells generated without viral integration. Science 322, 945–949. 
28. Perry A. R., Linch D. C. (1996). The history of bone-marrow transplantation. Blood Rev. 10, 215–219.
29. Austin E. B., Guttridge M., Pamphilon D., Watt S. M. (2008). The role of blood services and regulatory bodies in stem cell transplantation. Vox Sang. 94, 6–17.
30. Green H. (2008). The birth of therapy with cultured cells. Bioessays 30, 897–903. 
31. De Luca M., Pellegrini G., Green H. (2006). Regeneration of squamous epithelia from stem cells of cultured grafts. Review. Regen. Med. 1, 45–57.
32. Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Wells TH, Barrett JN, Grafton ST, Mazziotta JC, Eidelberg D, Rottenberg DA. (1990). Therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinson’s disease. Prog Brain Res. 1990;82:715-21.
33. Baetge EE.(1993). Neural stem cells for CNS transplantation. Ann N Y Acad Sci. 695:285-91.
34. Snyder EY, Macklis JD. (1995-1996). Multipotent neural progenitor or stem-like cells may be uniquely suited for therapy for some neurodegenerative conditions. Clin Neurosci. 3(5):310-6.
35. Dunnett SB, Kendall AL, Watts C, Torres EM. (1997). Neuronal cell transplantation for Parkinson’s and Huntington’s diseases. Br Med Bull. 53(4):757-76.
36. Dunnett S. B., Björklund A., Lindvall O. (2001). Cell therapy in Parkinson’s disease—stop or go? Review. Nat. Rev. Neurosci. 2, 365–369.
37. Wright B. L., Barker R. A. (2007). Established and emerging therapies for Huntington’s disease. Curr. Mol. Med. 7, 579–587.
38. Lowell S., Benchoua A., Heavey B., Smith A. G. (2006). Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol. 4, e121.
39. Mittoux V, Ouary S, Monville C, Lisovoski F, Poyot T, Conde F, Escartin C, Robichon R, Brouillet E, Peschanski M, Hantraye P. (2002). Corticostriatopallidal neuroprotection by adenovirus-mediated ciliary neurotrophic factor gene transfer in a rat model of progressive striatal degeneration. J Neurosci. 22(11):4478-86.
40. Raymon HK, Thode S, Gage FH. (1997). Application of ex vivo gene therapy in the treatment of Parkinson’s disease. Exp Neurol. 144(1):82-91.
41. Tuszynski MH. (2002). Growth-factor gene therapy for neurodegenerative disorders. Lancet Neurol. 1(1):51-7.
42. Gaspar H. B., Thrasher A. J. (2005). Gene therapy for severe combined immunodeficiencies. Expert Opin. Biol. Ther. 5, 1175–1182.
43. Pike-Overzet K., van der Burg M., Wagemaker G., van Dongen J. J., Staal F. J. (2007). New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol. Ther. 15, 1910–1916.
44. Mavilio F., et al. (2006). Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat. Med. 12, 1397–1402.
45. Lau D., Ogbogu U., Taylor B., Stafinski T., Menon D., Caulfield T. (2008). Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell 3, 591–594. 
46. Hyun I., et al. (2008). New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 3, 607–609. 
47. Zhou Q., Brown J., Kanarek A., Rajagopal J., Melton D. A. (2008). In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627–632.
48. Kamitakahara M., Ohtsuki C., Miyazaki T. (2008). Review paper: behavior of ceramic biomaterials derived from tricalcium phosphate in physiological condition. J. Biomater. Appl. 23, 197–212. 
49. Tsou YH, Khoneisser J, Huang PC, Xu X. (2016). Hydrogel as a bioactive material to regulate stem cell fate. Bioact Mater. 1(1):39–55.
50. Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. (2015). Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 3:2.