Future research and therapeutic applications of human stem cells: general, regulatory, and bioethical aspects

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There is much to be investigated about the specific characteristics of stem cells and about the efficacy and safety of the new drugs based on this type of cells, both embryonic as adult stem cells, for several therapeutic indications (cardiovascular and ischemic diseases,diabetes, hematopoietic diseases, liver diseases). Along with recent progress in transference of nuclei from human somatic cells, as well as iPSC technology, has allowed availability of lineages of all three germ layers genetically identical to those of the donor patient, which permits safe transplantation of organ-tissue-specific adult stem cells with no immune rejection. The main objective is the need for expansion of stem cell characteristics to maximize stem cell efficacy (i.e. the proper selection of a stem cell) and the efficacy (maximum effect) and safety of stem cell derived drugs. Other considerations to take into account in cell therapy will be the suitability of infrastructure and technical staff, biomaterials, production costs, biobanks, biosecurity, and the biotechnological industry. The general objectives in the area of stem cell research in the next few years, are related to identification of therapeutic targets and potential therapeutic tests, studies of cell differentiation and physiological mechanisms, culture conditions of pluripotent stem cells and efficacy and safety tests for stem cellbased drugs or procedures to be performed in both animal and human models in the corresponding clinical trials. A regulatory framework will be required to ensure patient accessibility to products and governmental assistance for their regulation and control. Bioethical aspects will be required related to the scientific and therapeutic relevance and cost of cryopreservation over time, but specially with respect to embryos which may ultimately be used for scientific uses of research as source of embryonic stem cells, in which case the bioethical conflict may be further aggravated.
1.Chagastelles PC, Nardi NB, Camassola M: Biology and applications of mesenchymal stem cells. Sci Prog 2010, 93:113-27. 2.Thiede MA: Stem Cell: applications and opportunities in drug discovery.Drug Discov World 2009, 10:9-16. 3. Ahrlund-Richter L, De Luca M, Marshak DR, Munsie M, Veiga A, Rao M: Isolation and production of cells suitable for human therapy: challenges ahead. Cell Stem Cell 2009, 4:20-6. 4.Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM: Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 1998, 282:1145-7. 5.Aflatoonian B, Moore H: Human primordial germ cells and embryonic germ cells, and their use in cell therapy. Curr Opin Biotechnol 2005, 16:530-5. 6. O’Donoghue K: Fetal Stem Cells. Best Pract Res Clin Obstet Gynaecol 2004, 18:853-75. 7. Alison MR, Islam S: Attributes of adult stem cells. J Pathol 2009,217:144-60. 8.Alison MR, Islam S, Lim S: Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol 2009, 217:282-98. 9.Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocites and hepatocytes. Nature 2003, 425:968-73. 10.Schäffler A, Büchler C: Concise review: adipose tissue-derived stromal cells basic and clinical implications for novel cell-based therapies. Stem Cells 2007, 25:818-27. 11. Docheva D, Popov C, Mutschler W, Schieker M: Human mensenchymal stem cells in contact with their environment: surface characteristics and their integrin system. J Cell Mol Med 2007, 11:21-38. 12.Prósper F, Verfaillie CM: Adult stem cells: Origin, characteristiques and perspectives of their therapeutic use. An Sist Sanit Navarr 2003, 26:345-56. 13.Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, Koç ON: Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant 2004, 33:597-604. 14. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M,Ringdén O: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004, 363:1439-41. 15.Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K: Mesenchymal stem cells for treatment of therapyresistant graft-versus-host disease. Transplantation 2006, 81:1390-7. 16.Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK: Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999, 5:309-13. 17.Bang OY, Lee JS, Lee PH, Lee G: Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005, 57:874-82. 18. Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, Kikuchi Y, Ito T, Okada T, Urabe M, Mizukami H, Kume A: Cell and gene therapy using mesenchymal stem cells (MSCs). J Autoimmun 2008, 30:121-7. 19.Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284:143-7. 20.Locke M, Windsor J, Dunbar PR: Human adipose-derived stem cells: isolation, characterization and applications in surgery. ANZ J Surg 2009, 79:235-44. 21.Rigotti G, Marchi A, Andrea Sbarbati A: Adipose-Derived Mesenchymal Stem Cells: Past, Present, and Future. Aesthet Plast Surg 2009, 33:271-3. 22.Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001, 7:211-28. 23.Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR: Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 2006, 291:R880-4. 24.Gimble JM, Katz AJ, Bunnell BA: Adipose-derived stem cells for regenerative medicine. Circ Res 2007, 100:1249-60. 25. Mizuno H: Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch 2009, 76:56-66. 26.Reiser J, Zhang XY, Hemenway CS, Mondal D, Pradhan L, La Russa VF:Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin Biol Ther 2005, 5:1571-84. 27.Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA: Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graftversus-host disease. Stem Cells 2006, 24:2582-91. 28.Fang B, Song Y, Liao L, Zhang Y, Zhao RC: Favorable response to humanadipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 2007, 39:3358-62. 29. Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M: Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 2009, 52:79-86. 30. Rigotti G, Marchi A, Galiè M, Baroni G, Benati D, Krampera M, Pasini A, Sbarbati A: Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg 2007, 119:1409-22. 31.Mizuno H: Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch 2009, 76:56-66. 32.Mizuno H: Adipose-derived stem and stromal cells for cell-based therapy: Current status of preclinical studies and clinical trials. Curr Opin Mol Ther 2010, 12:442-9. 33.Chao H, Hirschi KK: Hemato-vascular origins of endothelial progenitor cells? Microvasc Res 2010, 79:169-73. 34.Fougère-Deschatrette C: Plasticity of hepatic cell differentiation: bipotential adult mouse liver clonal cell lines competent to differentiate in vitro and in vivo. Stem Cells 2006, 24:2098-109. 35. Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, Mytinger J, Cao B, Gates C, Wernig A, Huard J: Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol 2002, 157:851-64. 36. Anversa P, Leri A, Rota M, Hosoda T, Bearzi C, Urbanek K, Kajstura J, Bolli R: Concise review: Stem cells, myocardial regeneration, and methodological artifacts. Stem Cells 2007, 25:589-601. 37.Méndez-Ferrer S, Ellison GM, Torella D, Nadal-Ginard B: Resident human cardiac stem cells: role in cardiac cellular homeostasis and potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med 2006, 3:(Suppl 1):S8-13. 38. Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C,Holtas S, van Roon-Mom WM, Björk-Eriksson T, Nordborg C, Frisén J,Dragunow M, Faull RL, Eriksson PS: Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular Extension. Science 2007, 315:1243-9. 39.Galli R, Gritti A, Bonfanti L, Vescovi AL: Neural Stem Cells An Overview. Circ Res 2003, 92:598-608. 40.Pardal R, Ortega-Sáenz P, Durán R, López-Barneo J: Glia-like Stem Cells Sustain Physiologic Neurogenesis in the Adult Mammalian Carotid Body. Cell 2007, 131:364-77. 41.Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural Stem Cells in the adult mammalian Brain. Cell 1999, 97:703-16. 42. Watt FM, Lo Celso C, Silva-Vargas V: Epidermal stem cells: an update. Curr Opin Genet Dev 2006, 16:518-24. 43. Sommer CA, Mostoslavsky G: Experimental approaches for the generation of induced pluripotent stem cells. Stem Cell Res Ther 2010, 1:26]. 44. Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126:663-76. 45. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL,Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA: Induced Liras Journal of Translational Medicine 2010, 8:131 Page 13 of 15pluripotent stem cell lines derived from human somatic cells. Science 2007, 318:1917-20. 46.Okita K, Hong H, Takahashi K, Yamanaka S: Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nat Protoc 2010, 5:418-28. 47.Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K: Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009, 458:771-5. 48.Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R,Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A:PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009, 458:766-70. 49.Yamanaka S: Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 2007, 1:39-49. 50. Alternative sources of human pluripotent stem cells. White paper: The President’s Council on Bioethics. Washington, D.C 2005 []. 51. 2008 Amendments to the National Academies’ guidelines for human embryonic stem cell research National Research Council and Institute of Medicine. National Academy Press; 2008 [ = 12260&page = 1]. 52. Amabile G, Meissner A: Induced pluripotent stem cells: current progress and potential for regenerative medicine. Trends Mol Med 2009, 15:59-68. 53. Hochedlinger K, Plath K: Epigenetic reprogramming and induced pluripotency. Development 2009, 136:509-23. 54. Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y: Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 2008, 283:31601-7. 55. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K: Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008, 321:1218-21. 56. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ: Disease-specific induced pluripotent stem cells. Cell 2008, 134:877-86. 57. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN: Induced pluripotent stem cells from a spinal muscular atrophy patient.Nature 2009, 457:277-80. 58.Caspi O, Itzhaki I, Kehat I, Gepstein A, Arbel G, Huber I, Satin J, Gepstein L: In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes. Stem Cells Dev 2009, 18:161-72. 59.Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flügel L, Dorn T, Goedel A, Höhnke C, Hofmann F, Seyfarth M, Sinnecker D, Schömig A, Laugwitz KL: Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome. N Engl J Med 2010, 363:1397-409. 60.Razvi ES, Oosta GM: Stem Cells for cellular therapy space. Drug Discov Today 2010, 11:37-40. 61. Hatzimichael E, Tuthill M: Hematopoietic stem cell transplantation. Stem Cells Cloning: Advances and Applications 2010, 3:105-17. 62.Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, Kikuchi Y, Ito T, Okada T, Urabe M, Mizukami H, Kume A: Cell and gene therapy using mesenchymal stem cells (MSCs). J Autoimmun 2008, 30:121-7. 63.Rigotti G, Marchi A, Andrea Sbarbati A: Adipose-Derived Mesenchymal Stem Cells: Past, Present, and Future. Aesthet Plast Surg 2009, 33:271-3. 64.Follenzi A, Benten D, Novikoff P, Faulkner L, Raut S, Gupta S: Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice. J Clin Invest 2008, 118:935-45. 65.Xu D, Alipio Z, Fink LM, Adcock DM, Yang J, Ward DC, Ma Y: Phenotypic correction of murine hemophilia A using an iPSCs cell-based therapy. Proc Natl Acad Sci USA 2009, 106:808-13. 66. Liras A: Gene therapy for haemophilia: The end of a “royal pathology” in the third millennium? Haemophilia 2001, 7:441-5. 67. Liras A, Olmedillas S: Gene therapy for haemophilia...yes, but...with nonviral vectors? Haemophilia 2009, 15:811-6. 68. Olmedillas S, Liras A, Migueliz I, García-Olmo D, García Arranz M, Tros de Ilarduya C: In vitro gene transfer to adipose mesenchymal stem cells by improved transferrin-lipoplexes and polyplexes. Preliminary studies:cytotoxicity and transfection. Proceedings of the IX Congress of the Spanish Society of Industrial Pharmacy and Pharmaceutics University of Navarra (Spain); 2009, 211-3. 69. Fagoonee S, Hobbs RM, De Chiara L, Cantarella D, Piro RM, Tolosano E, Medico E, Provero P, Pandolfi PP, Silengo L, Altruda F: Generation of Functional Hepatocytes From Mouse Germ Line Cell-Derived Pluripotent Stem Cells In Vitro. Stem Cells Dev 2010, 19:1183-94. 70. Nehlin JO, Barington T: Strategies for future histocompatible stem cell therapy. Biogerontology 2009, 10:339-76. 71. Ronti T, Lupattelli G, Mannarino E: The endocrine function of adipose tissue: an update. Clin Endocrinol 2006, 64:355-65. 72.Lombardo E, DelaRosa O, Mancheño-Corvo P, Menta R, Ramírez C, Büscher D: Toll-Like Receptor-Mediated Signaling in Human Adipose-Derived Stem Cells: Implications for Immunogenicity and Immunosuppressive Potential. Tissue Eng Part A 2009, 15:1579-89. 73.Gonzalez-Rey E, Gonzalez MA, Varela N, O’Valle F, Hernandez-Cortes P, Rico L, Büscher D, Delgado M: Human adipose-derived mesenchymal stem cells reduce inflammatory and T-cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 2010, 69:241-8. 74. Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M: Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009, 58:929-39. 75. Uccelli A, Pistoia V, Moretta L: Mesenchymal stem cells: A new strategy for immunosuppression? Trends Immunol 2007, 28:219-26. 76. Wan CD, Cheng R, Wang HB, Liu T: Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model. Hepatob Pancreatic Dis Int 2008, 7:29-33. 77.Pistoia V, Raffaghello L: Potential of mesenchymal stem cells for the therapy of autoimmune diseases. Expert Rev Clin Immunol 2010, 6:211-8. 78.Cellular and Gene Therapy Products. U.S.Food and Drug Administration.]. 79.Kasper CK, Buzin CH: Mosaics and haemophilia. Haemophilia 2009, 15:,1181-6. 80. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.]. 81. European Pharmacopoeia.]. 82. The United States Pharmacopeia. []. 83. Good Manufacturing Practice for Pharmaceutical Manufacturers. []. 84. FACT-JACIE International Standards for Cellular Therapy Product Collection, Processing, and Administration (Foundation for the Accreditation of Cellular Therapy (FACT)-Joint Accreditation Committee of International Society for Cellular Therapy (ISCT) and European Group for Blood and Marrow Transplantation (EBMT) (JACIE). []. 85.Fierabracci A: Recents patents for isolating, delivering and tracking adult stem cells in regenerative medicine. Recent Pat Drug Deliv Formul 2010, 4:105-13. 86.Lim GJ, Zare S, Van Dyke M, Atala A: Cell microencapsulation. Adv Exp Med Biol 2010, 670:126-36. 87.Santos E, Zarate J, Orive G, Hernández RM, Pedraz JL: Biomaterials in cell microencapsulation. Adv Exp Med Biol 2010, 670:5-21. 88.Mendelsohn A, Desai T: Inorganic nanoporous membranes for immunoisolated cell-based drug delivery. Adv Exp Med Biol 2010, 670:104-25. 89.De Vos P, Spasojevic M, Faas MM: Treatment of diabetes with encapsulated islets. Adv Exp Med Biol 2010, 670:38-53. 90.Vayssade M, Nagel MD: Stromal cells. Front Biosci 2009, 14:210-24. 91.Ignjatovic NL, Ajdukovic ZR, Savic VP, Uskokovic DP: Size effect of calcium phosphate coated with poly-DL-lactide-co-glycolide on healing processes in bone reconstruction. J Biomed Mater Res Part B 2010,94:108-17. 92.McQuade K, Gable D, Pearl G, Theune B, Black S: Four-year randomized prospective comparison of percutaneous ePTFE/nitinol self-expanding stent graft versus prosthetic femoral-popliteal bypass in the treatment of superficial femoral artery occlusive disease. J Vasc Surg 2010, 52:584-90. 93.Yao L, Wang S, Cui W, Sherlock R, O’Connell C, Damodaran G, Gorman AWindebank A, Pandit A: Effect of functionalized micropatterned PLGA on guided neurite growth. Acta Biomater 2009, 5:580-8.