New perspectives in human stem cell therapeutic research

Alan Trounson, Alan Trounson

Abstract

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating beta islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.

Figures

Figure 1
Figure 1
Human stem cell transplants. Bone marrow cells are mobilized and recovered for autologos transplantation for a number of applications, including cancer, blood diseases, stroke and multiple sclerosis. Allogenic stem cells are frequently recovered from the placenta and umbilical cord. Mesenchymal stem cells are used for immune suppression and inflammatory conditions. Neural stem cells are of fetal origin or differentiated from embryonic stem (ES) cells and induced pluripotential stem (iPS) cells. Both ES and iPS cells are poised for clinical trials for repair of spinal injury, macular degeneration, diabetes and cancer.

References

    1. Kovacic JC, Macdonald P, Feneley MP, Muller DW, Freund J, Dodds A, Milliken S, Tao H, Itescu S, Moore J, Ma D, Graham RM. Safety and efficacy of consecutive cycles of granulocyte-colony stimulating factor, and an intracoronary CD133+ cell infusion in patients with chronic refractory ischemic heart disease: the G-CSF in angina patients with IHD to stimulate neovascularization (GAIN I) trial. Am Heart J. 2008;156:954–963. doi: 10.1016/j.ahj.2008.04.034.
    1. Dill T, Schächinger V, Rolf A, Möllmann S, Thiele H, Tillmanns H, Assmus B, Dimmeler S, Zeiher AM, Hamm C. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J. 2009;157:541–547. doi: 10.1016/j.ahj.2008.11.011.
    1. Sekiguchi H, Ii M, Losordo DW. The relative potency and safety of endothelial progenitor cells and unselected mononuclear cells for recovery from myocardial infarction and ischemia. Am J Physiol Cell Physiol. 2009;219:235–242.
    1. Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I. Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc. 2009
    1. Brooke G, Rossetti T, Pelekanos R, Ilic N, Murray P, Hancock S, Antonenas V, Huang G, Gottlieb D, Bradstock K, Atkinson K. Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials. Br J Haematol. 2009;144:571–579. doi: 10.1111/j.1365-2141.2008.07492.x.
    1. Moodley Y, Atienza D, Manuelpillai U, Tchongue J, Samuel CS, Ilancheran S, Boyd R, Trounson A. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Path. 2009
    1. Narimatsu H, Miyamura K, Iida H, Hamaguchi M, Uchida T, Morishita Y, Nagoya Blood and Marrow Transplantation Group (NBMTG) Early central nervous complications after umbilical cord blood transplantation for adults. Biol Blood Marrow Transplant. 2009;15:92–100. doi: 10.1016/j.bbmt.2008.11.005.
    1. Gonzalo-Daganzo R, Regidor C, Martín-Donaire T, Rico MA, Bautista G, Krsnik I, Forés R, Ojeda E, Sanjuán I, García-Marco JA, Navarro B, Gil S, Sánchez R, Panadero N, Gutiérrez Y, García-Berciano M, Pérez N, Millán I, Cabrera R, Fernández MN. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy. 2009;11:278–288. doi: 10.1080/14653240902807018.
    1. Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, Oyama Y, Russell EJ, Stern J, Muraro P, Rose J, Testori A, Bucha J, Jovanovic B, Milanetti F, Storek J, Voltarelli JC, Burns WH. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8:244–253. doi: 10.1016/S1474-4422(09)70017-1.
    1. Nasef A, Ashammakhi N, Fouillard L. Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Int J Lab Hematol. 2009;31:9–19. doi: 10.1111/j.1751-553X.2007.00997.x.
    1. Troeger A, Meisel R, Moritz T, Dilloo D. Immunotherapy in allogeneic hematopoietic stem cell transplantation – not just a case for effector cells. Bone Marrow Transplant. 2005:S59–S64. doi: 10.1038/sj.bmt.1704849.
    1. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O, Developmental Committee of the European Group for Blood and Marrow Transplantation Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–1586. doi: 10.1016/S0140-6736(08)60690-X.
    1. Iyer SS, Co C, Rojas M. Mesenchymal stem cells and inflammatory lung diseases. Panminerva Med. 2009;51:5–16.
    1. Li M, Sun K, Welniak LA, Murphy WJ. Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease. Expert Opin Pharmacother. 2008;9:2305–2316. doi: 10.1517/14656566.9.13.2305.
    1. Crop MJ, Baan CC, Korevaar SS, Ijzermans JN, Alwayn IP, Weimar W, Hoogduijn MJ. Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients. Transplantation. 2009;87:896–906. doi: 10.1097/TP.0b013e31819b3d72.
    1. Torrente Y, Polli E. Mesenchymal stem cell transplantation for neurodegenerative diseases. Cell Transplant. 2008;17:1103–1113. doi: 10.3727/096368908787236576.
    1. England T, Martin P, Bath PMW. Stem cells for enhancing recovery after stroke: a review. Int J Stroke. 2009;4:101–110. doi: 10.1111/j.1747-4949.2009.00253.x.
    1. Wechsler L, Steindler D, Borlongan C, Chopp M, Savitz S, Deans R, Caplan L, Hess D, Mays RW, Boltze J, Boncoraglio G, Borlongan CV, Caplan LR, Carmichael ST, Chopp M, Davidoff AW, Deans RJ, Fisher M, Hess DC, Kondziolka D, Mays RW, Norrving B, Parati E, Parent J, Reynolds BA, Gonzalez-Rothi LJ, Savitz S, Sanberg P, Schneider D, Sinden JD, et al. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40:510–515.
    1. Wynn RF, Wraith JE, Mercer J, O'Meara A, Tylee K, Thornley M, Church HJ, Bigger BW. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr. 2009;154:609–611. doi: 10.1016/j.jpeds.2008.11.005.
    1. Rath P, Shi H, Maruniak JA, Litofsky NS, Maria BL, Kirk MD. Stem cells as vectors to deliver HSV/tk gene therapy for malignant gliomas. Curr Stem Cell Res Ther. 2009;4:44–49. doi: 10.2174/157488809787169138.
    1. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D, Leider-Trejo L, Toren A, Constantini S, Rechavi G. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009;6:e1000029. doi: 10.1371/journal.pmed.1000029.
    1. Couzin J. Biotechnology. Celebration and concern over US trial of embryonic stem cells. Science. 2009;323:568. doi: 10.1126/science.323.5914.568.
    1. Barde Y. Caution urged in trial of stem cells to treat spinal-cord injury. Nature. 2009;457:516. doi: 10.1038/457516a.
    1. Hyun I, Lindvall O, Ahrlund-Richter L, Cattaneo E, Cavazzana-Calvo M, Cossu G, De Luca M, Fox IJ, Gerstle C, Goldstein RA, Hermerén G, High KA, Kim HO, Lee HP, Levy-Lahad E, Li L, Lo B, Marshak DR, McNab A, Munsie M, Nakauchi H, Rao M, Rooke HM, Valles CS, Srivastava A, Sugarman J, Taylor PL, Veiga A, Wong AL, Zoloth L, et al. New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell. 2008;3:607–609. doi: 10.1016/j.stem.2008.11.009.
    1. Yamanaka S. A fresh look at iPS cells. Cell. 2009;137:13–17. doi: 10.1016/j.cell.2009.03.034.
    1. Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Schöler HR, Duan L, Ding S. Generation of induced pluripotent stem cells using recombinant protein. Cell Stem Cell. 2009;4:381–4. doi: 10.1016/j.stem.2009.04.005.
    1. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D'Amour KA, Carpenter MK, Baetge EE. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26:397–398. doi: 10.1038/nbt1393.
    1. Pal R. Embryonic stem (ES) cell-derived cardiomyocytes: a good candidate for cell therapy applications. Cell Biol Int. 2009;33:325–326. doi: 10.1016/j.cellbi.2008.12.001.
    1. Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson's disease. Trends Pharmacol Sci. 2009;30:260–267. doi: 10.1016/j.tips.2009.03.001.
    1. Basma H, Soto-Gutiérrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Alvarez N, Wong RJ, Roy-Chowdhury J, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology. 2009;136:990–999. doi: 10.1053/j.gastro.2008.10.047.
    1. Vugler A, Carr AJ, Lawrence J, Chen LL, Burrell K, Wright A, Lundh P, Semo M, Ahmado A, Gias C, da Cruz L, Moore H, Andrews P, Walsh J, Coffey P. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol. 2008;214:347–361. doi: 10.1016/j.expneurol.2008.09.007.

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