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Critical appraisal of stem cell therapy in peripheral arterial disease: Do current scientific breakthroughs offer true promise or false hope?

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DOI: 10.4236/jbise.2014.72011    4,094 Downloads   5,424 Views   Citations

ABSTRACT

Over the last forty years in the field of peripheral arterial disease, there has been a plethora of research into cell-based therapies for tissue repair, regeneration and angiogenesis, progressing from protein-based therapies to gene therapies to stem cell research. Initial pre-clinical research successes have given birth to a whole industry, aimed at translating these laboratory hopes into clinical successes. However, heretofore these expected clinical results have failed to materialize, in part due to the lack of attention to the ischaemic desert like tissue and systemically diseased patient into which the stem cells are being implanted. Unsatisfactory clinical outcomes on the treatment of Critical Limb Ischaemia (CLI) have forced researchers to direct their efforts to the less intimidating challenge of claudication and to lower their clinical outcome thresholds from superior to “non-inferior”. Major questions on safety and durability have also arisen. What needs to be objectively established is the impact on the net health outcome of these therapies. Infusion or injection for stem cell therapy is still considered experimental and investigational. In this review we examine the clinical evidence for angiogenic therapies, focusing specifically on stem cell trials, in an attempt to answer the question “Is stem cell therapy a failed experiment or will there be light at the end of the tunnel?”

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Sultan, S. and Hynes, N. (2014) Critical appraisal of stem cell therapy in peripheral arterial disease: Do current scientific breakthroughs offer true promise or false hope?. Journal of Biomedical Science and Engineering, 7, 75-85. doi: 10.4236/jbise.2014.72011.

References

[1] Behrendt, D. and Ganz, P. (2002) Endothelial function. From vascular biology to clinical applications. American Journal of Cardiology, 90, 40L-48L.
http://dx.doi.org/10.1016/S0002-9149(02)02963-6
[2] Ferrara, N. (2002) Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Seminars in Oncology, 29, 10-14.
http://dx.doi.org/10.1016/S0093-7754(02)70064-X
[3] Bradbury, A.W., Adam, D.J., Bell, J., Forbes, J.F., Fowkes, F.G., Gillespie, I., Ruckley, C.V. and Raab, G.M. (2010) BASIL trial Participants. BASIL trial Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Analysis of amputation free and overall survival by treatment received. Journal of Vascular Surgery, 51, 18S-31S.
http://dx.doi.org/10.1016/j.jvs.2010.01.074
[4] Kawamoto, A., Katayama, M., Handa, N., Kinoshita, M., Takano, H., Horii, M., Sadamoto, K., Yokoyama, A., Yamanaka, T., Onodera, R., Kuroda, A., Baba, R., Kaneko, Y., Tsukie, T., Kurimoto, Y., Okada, Y., Kihara, Y., Morioka, S., Fukushima, M. and Asahara, T. (2009) Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: A phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells, 27, 2857-2864.
http://dx.doi.org/10.1002/stem.207
[5] Sultan, S. and Hynes, N. (2009) Five-year Irish trial of CLI patients with TASC II type C/D lesions undergoing subintimal angioplasty or bypass surgery based on plaque echolucency. Journal of Endovascular Therapy, 16, 270-283.
http://dx.doi.org/10.1583/08-2581.1
[6] Sultan, S., Tawfick, W. and Hynes, N. (2013) Cool excimer laser-assisted angioplasty (CELA) and tibial balloon angioplasty (TBA) in management of infragenicular arterial occlusion in critical lower limb ischemia (CLI). Vascular and Endovascular Surgery, 47, 179-191.
http://dx.doi.org/10.1177/1538574413478473
[7] Sultan, S., Hamada, N., Soylu, E., Fahy, A., Hynes, N. and Tawfick, W. (2011) Sequential compression biomechanical device in patients with critical limb ischemia and nonreconstructible peripheral vascular disease. Journal of Vascular Surgery, 54, 440-446.
http://dx.doi.org/10.1016/j.jvs.2011.02.057
[8] Tawfick, W.A., Hamada, N., Soylu, E., Fahy, A., Hynes, N. and Sultan, S. (2013) Sequential compression biomechanical device versus primary amputation in patients with critical limb ischemia. Vascular and Endovascular Surgery, 47, 532-539.
http://dx.doi.org/10.1177/1538574413499413
[9] Hammer, A. and Steiner, S. (2013) Gene therapy for therapeutic angiogenesis in peripheral arterial disease—A systematic review and meta-analysis of randomized, controlled trials. Vasa, 42, 331-339.
http://dx.doi.org/10.1024/0301-1526/a000298
[10] Sen, S., Conroy, S., Hynes, S.O., McMahon, J., O’Doherty, A., Bartlett, J.S., Akhtar, Y., Adegbola, T., Connolly, C.E., Sultan, S., Barry, F., Katusic, Z.S. and O’Brien, T. (2008) Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5. The Journal of Gene Medicine, 10, 143-151.
http://dx.doi.org/10.1002/jgm.1133
[11] Stocca, A., O’Toole, D., Hynes, N., Hynes, S.O., Mashayekhi, K., McGinley, L., O’Connell, E., Coleman, C., Sultan, S., Duffy, A., Tunev, S. and O’Brien, T. (2012) A role for MRP8 in in stent restenosis in diabetes. Atherosclerosis, 221, 325-332.
http://dx.doi.org/10.1016/j.atherosclerosis.2012.01.036
[12] Henry, T.D., Annex, B.H., McKendall, G.R., Azrin, M.A., Lopez, J.J., Giordano, F.J., Shah, P.K., Willerson, J.T., Benza, R.L., Berman, D.S., Gibson, C.M., Bajamonde, A., Rundle, A.C., Fine, J. and McCluskey, E.R. (2003) VIVA Investigators. The VIVA trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis. Circulation, 107, 1359-1365.
http://dx.doi.org/10.1161/01.CIR.0000061911.47710.8A
[13] Lederman, R.J., Mendelsohn, F.O., Anderson, R.D., Saucedo, J.F., Tenaglia, A.N., Hermiller, J.B., Hillegass, W.B., Rocha-Singh, K., Moon, T.E., Whitehouse, M.J. and Annex, B.H. (2002) TRAFFIC Investigators. Therapeutic Angiogenesis with Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (the TRAFFIC study): A randomised trial. Lancet, 359, 2053-2058.
http://dx.doi.org/10.1016/S0140-6736(02)08937-7
[14] Menasché, P., Alfieri, O., Janssens, S., McKenna, W., Reichenspurner, H., Trinquart, L., Vilquin, J.T., Marolleau, J.P., Seymour, B., Larghero, J., Lake, S., Chatellier, G., Solomon, S., Desnos, M. and Hagège, A.A. (2008) The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: First randomized placebo-controlled study of myoblast transplantation. Circulation, 117, 1189-1200.
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.734103
[15] Kastrup, J., Jørgensen, E., Rück, A., Tägil, K., Glogar, D., Ruzyllo, W., Bøtker, H.E., Dudek, D., Drvota, V., Hesse, B., Thuesen, L., Blomberg, P., Gyöngyösi, M. and Sylvén, C. (2005) Euroinject One Group. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study: The Euroinject One trial. Journal of the American College of Cardiology, 45, 982-988.
http://dx.doi.org/10.1016/j.jacc.2004.12.068
[16] Kusumanto, Y.H., van Weel, V., Mulder, N.H., Smit, A.J., van den Dungen, J.J., Hooymans, J.M., Sluiter, W.J., Tio, R.A., Quax, P.H., Gans, R.O., Dullaart, R.P. and Hospers, G.A. (2006) Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: A double-blind randomized trial. Human Gene Therapy, 17, 683-691. http://dx.doi.org/10.1089/hum.2006.17.683
[17] Lederman, R.J., Mendelsohn, F.O., Anderson, R.D., et al. (2002) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): A randomised trial. Lancet, 359, 2053-2058.
http://dx.doi.org/10.1016/S0140-6736(02)08937-7
[18] Rajagopalan, S., Mohler III, E.R., Lederman, R.J., et al. (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease. Circulation, 108, 1933-1938.
http://dx.doi.org/10.1161/01.CIR.0000093398.16124.29
[19] Royen, N., Schirmer, S.H., Atasever, B., et al. (2005) START Trial: A pilot study on stimulation of arteriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. Circulation, 112, 1040-1046.
http://dx.doi.org/10.1161/CIRCULATIONAHA.104.529552
[20] Belch, J., Hiatt, W.R., Baumgartner, I., Driver, I.V., Nikol, S., Norgren, L. and Van Belle, E. (2011) TAMARIS Committees and Investigators. Effect of fibroblast growth factor NV1FGF on amputation and death: A randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet, 377, 1929-1937.
http://dx.doi.org/10.1016/S0140-6736(11)60394-2
[21] Nikol, S., Baumgartner, I., Van Belle, E., Diehm, C., Visoná, A., Capogrossi, M.C., Ferreira-Maldent, N., Gallino, A., Wyatt, M.G., Wijesinghe, L.D., Fusari, M., Stephan, D., Emmerich, J., Pompilio, G., Vermassen, F., Pham, E., Grek, V., Coleman, M. and Meyer, F. (2008) TALIS-MAN 201 investigators. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Molecular Therapy, 16, 972-978.
http://dx.doi.org/10.1038/mt.2008.33
[22] Collinson, D.J. and Donnelly, R. (2004) Therapeutic angiogenesis in peripheral arterial disease: Can biotechnology produce an effective collateral circulation? European Journal of Vascular and Endovascular Surgery, 28, 9-23.
http://dx.doi.org/10.1016/j.ejvs.2004.03.021
[23] Ylä-Herttuala, S. (2013) Cardiovascular gene therapy with vascular endothelial growth factors. Gene, 525, 217-219.
http://dx.doi.org/10.1016/j.gene.2013.03.051
[24] Ghosh, R., Walsh, S.R., Tang, T.Y., Noorani, A. and Hayes, P.D. (2008) Gene therapy as a novel therapeutic option in the treatment of peripheral vascular disease: Systematic review and meta-analysis. International Journal of Clinical Practice, 62, 1383-1390.
http://dx.doi.org/10.1111/j.1742-1241.2008.01842.x
[25] Hammer, A. and Steiner, S. (2013) Gene therapy for therapeutic angiogenesis in peripheral arterial disease—A systematic review and meta-analysis of randomized, controlled trials. Vasa, 42, 331-339.
http://dx.doi.org/10.1024/0301-1526/a000298
[26] Grochot-Przeczek, A., Dulak, J. and Jozkowicz, A. (2013) Therapeutic angiogenesis for revascularization in peripheral artery disease. Gene, 525, 220-228.
http://dx.doi.org/10.1016/j.gene.2013.03.097
[27] Tateishi-Yuyama, E., Matsubara, H., Murohara, T., Ikeda, U., Shintani, S., Masaki, H., et al. (2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bonemarrow cells: A pilot study and a randomised controlled trial. Lancet, 360, 427-435.
http://dx.doi.org/10.1016/S0140-6736(02)09670-8
[28] Huang, P., Li, S., Han, M., Xiao, Z., Yang, R. and Han, Z.C. (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care, 28, 2155-2160.
http://dx.doi.org/10.2337/diacare.28.9.2155
[29] Arai, M., Misao, Y., Nagai, H., Kawasaki, M., Nagashima, K., Suzuki, K., et al. (2006) Granulocyte colony-stimulating factor: A noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. Circulation Journal, 70, 1093-1098.
http://dx.doi.org/10.1253/circj.70.1093
[30] Bartsch, T., Brehm, M., Zeus, T., Kögler, G., Wernet, P. and Strauer, B.E. (2007) Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clinical research in cardiology: Official journal of the German Cardiac Society, 96, 891-899.
http://dx.doi.org/10.1007/s00392-007-0569-x
[31] Cobellis, G., Silvestroni, A., Lillo, S., Sica, G., Botti, C., Maione, C., Schiavone, V., Rocco, S., Brando, G. and Sica, V. (2008) Long-term effects of repeated autologous transplantation of bone marrow cells in patients affected by peripheral arterial disease. Bone Marrow Transplantation, 42, 667-672.
http://dx.doi.org/10.1038/bmt.2008.228
[32] Procházka, V., Gumulec, J., Jaluvka, F., Salounová, D., Jonszta, T., Czerny, D., Krajca, J., Urbanec, R., Klement, P., Martinek, J. and Klement, G.L. (2010) Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplantation, 19, 1413-1424. http://dx.doi.org/10.3727/096368910X514170
[33] Walter, D.H., Krankenberg, H., Balzer, J.O., Kalka, C., Baumgartner, I., Schlüter, M., Tonn, T., Seeger, F., Dimmeler, S., Lindhoff-Last, E. and Zeiher, A.M. (2011) Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: A randomized-start, placebo-controlled pilot trial (PROVA-SA). Circulation: Cardiovascular Interventions, 4, 26-37.
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.110.958348
[34] Iafrati, M.D., Hallett, J.W., Geils, G., Pearl, G., Lumsden, A., Peden, E., Bandyk, D., Vijayaraghava, K.S., Radhakrishnan, R., Ascher, E., Hingorani, A. and Roddy, S. (2011) Early results and lessons learned from a multi-center, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. Journal of Vascular Surgery, 54, 1650-1658.
http://dx.doi.org/10.1016/j.jvs.2011.06.118
[35] Idei, N., Soga, J., Hata, T., Fujii, Y., Fujimura, N., Mikami, S., Maruhashi, T., Nishioka, K., Hidaka, T., Kihara, Y., Chowdhury, M., Noma, K., Taguchi, A., Chayama, K., Sueda, T. and Higash, Y. (2011) Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: A comparison of atherosclerotic peripheral arterial disease and Buerger disease. Circulation: Cardiovascular Interventions, 4, 15-25.
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.110.955724
[36] Benoit, E., O’Donnell Jr., T.F., Iafrati, M.D., Asher, E., Bankyk, D.F., Hallett, J.W., Lumsden, A.B., Pearl, G.J., Roddy, S.P., Vijayaraghavan, K. and Patel, A.N. (2011) The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: Implications for clinical trial design. Journal of Translational Medicine, 9, 165.
[37] Powell, R.J., Comerota, A.J., Berceli, S.A., Guzman, R., Henry, T.D., Tzeng, E., et al. (2011) Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. Journal of Vascular Surgery, 54, 1032-1041.
http://dx.doi.org/10.1016/j.jvs.2011.04.006
[38] Powell, R.J., Marston, W.A., Bercell, S.A., Guzman, R., Henry, T.D., Longcore, A.T., Stern, T.P., Watling, S. and Bartel, R.L. (2012) Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: The randomized, double-blind, placebo-controlled RESTORE-CLI trial. Molecular Therapy, 20, 1280-1286.
http://dx.doi.org/10.1038/mt.2012.52
[39] Losordo, D.W., Kibbe, M.R., Mendelsohn, F., Marston, W., Driver, V.R., Sharafuddin, M., et al. (2012) A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circulation: Cardiovascular Interventions, 5, 821-830.
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.112.968321
[40] Fadini, G.P., Agostini, C. and Avogaro, A. (2010) Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis, 209, 10-17.
http://dx.doi.org/10.1016/j.atherosclerosis.2009.08.033
[41] Sekiguchi, H., Ii, M. and Losordo, D.W. (2009) The relative potency and safety of endothelial progenitor cells and unselected mononuclear cells for recovery from myocardial infarction and ischemia. Journal of Cellular Physiology, 219, 235-242.
http://dx.doi.org/10.1002/jcp.21672
[42] Tateno, K., Minamino, T., Toko, H., Akazawa, H., Shimizu, N., Takeda, S., Kunieda, T., Miyauchi, H., Oyama, T., Matsuura, K., Nishi, J., Kobayashi, Y., Nagai, T., Kuwabara, Y., Iwakura, Y., Nomura, F., Saito, Y. and Komuro, I. (2006) Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circulation Research, 98, 1194-1202.
http://dx.doi.org/10.1161/01.RES.0000219901.13974.15
[43] Amano, K., Okigaki, M., Adachi, Y., Fujiyama, S., Mori, Y., Kosaki, A., Iwasaka, T. and Matsubara, H. (2004) Mechanism for IL-1β-mediated neovascularization unmasked by IL-1β knock-out mice. Journal of Molecular and Cellular Cardiology, 36, 469-480.
http://dx.doi.org/10.1016/j.yjmcc.2004.01.006
[44] Gupta, P.K., Chullikana, A., Parakh, R., Desai, S., Das, A., Gottipamula, S., Krishnamurthy, S., Anthony, N., Pherwani, A. and Majumdar, A.S. (2013) A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. Journal of Translational Medicine, 11, 143.
http://dx.doi.org/10.1186/1479-5876-11-143
[45] Matoba, S., Tatsumi, T., Murohara, T., Imaizumi, T., Katsuda, Y., Ito, M., Saito, Y., Uemura, S., Suzuki, H., Fukumoto, S., Yamamoto, Y., Onodera, R., Teramukai, S., Fukushima, M. and Matsubara, H. (2008) TACT Follow-up Study Investigators. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. American Heart Journal, 156, 1010-1018.
http://dx.doi.org/10.1016/j.ahj.2008.06.025
[46] Blum, B. and Benvenisty, N. (2008) The tumorigenicity of human embryonic stem cells. Advances in Cancer Research, 100, 133-158.
http://dx.doi.org/10.1016/S0065-230X(08)00005-5
[47] Barber, C.L. and Iruela-Arispe, M.L. (2006) The ever-elusive endothelial progenitor cell: Identities, functions and clinical implications. Pediatric Research, 59, 26R-32R.
http://dx.doi.org/10.1203/01.pdr.0000203553.46471.18
[48] Brixius, K., Funcke, F., Graf, C. and Bloch, W. (2006) Endothelial progenitor cells: A new target for the prevention of cardiovascular diseases. European Journal of Preventive Cardiology, 13, 705-710.
http://dx.doi.org/10.1097/01.hjr.0000221862.34662.31
[49] Gimble, J.M., Katz, A.J. and Bunnell, B.A. (2007) Adipose-derived stem cells for regenerative medicine. Circulation Research, 100, 1249-1260.
http://dx.doi.org/10.1161/01.RES.0000265074.83288.09
[50] Loffredo, F. and Lee, R.T. (2008) Therapeutic vasculo-genesis: It takes two. Circulation Research, 103, 128-130. http://dx.doi.org/10.1161/CIRCRESAHA.108.180604
[51] Roche, R., Hoareau, L., Mounet, F. and Festy, F. (2007) Adult stem cells for cardiovascular diseases: The adipose tissue potential. Expert Opinion on Biological Therapy, 7, 791-798.
http://dx.doi.org/10.1517/14712598.7.6.791
[52] Asahara, T. and Kawamoto, A. (2004) Endothelial progenitor cells for postnatal vasculogenesis. American Journal of Physiology-Cell Physiology, 287, C572-C579.
http://dx.doi.org/10.1152/ajpcell.00330.2003
[53] Spinetti, G., Kraenkel, N., Emanueli, C. and Madeddu, P. (2008) Diabetes and vessel wall remodelling: From mechanistic insights to regenerative therapies. Cardiovascular Research, 78, 265-273.
http://dx.doi.org/10.1093/cvr/cvn039
[54] Tengi, M., Geng, Z., Huang, L. and Zhao, X. (2012) Stem cell transplantation in cardiovascular disease: An update. Journal of International Medical Research, 40, 833-838. http://dx.doi.org/10.1177/147323001204000301
[55] Leeper, N.J., Hunter, A.L. and Cooke, J.P. (2010) Stem cell therapy for vascular regeneration. Adult, embryonic, and induced pluripotent stem cells. Circulation, 122, 517-526. http://dx.doi.org/10.1161/CIRCULATIONAHA.109.881441
[56] Okita, K., Ichisaka, T. and Yamanaka, S. (2007) Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313-317.
http://dx.doi.org/10.1038/nature05934
[57] Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. and Yamanaka, S. (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322, 949-953.
http://dx.doi.org/10.1126/science.1164270
[58] Sommer, C.A., Stadtfeld, M., Murphy, G.J., Hochedlinger, K., Kotton, D.N. and Mostoslavsky, G. (2009) Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells, 27, 543-549.
http://dx.doi.org/10.1634/stemcells.2008-1075
[59] Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. and Hochedlinger, K. (2008) Induced pluripotent stem cells generated without viral integration. Science, 322, 945-949.
http://dx.doi.org/10.1126/science.1162494
[60] Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W. and Melton, D.A. (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269-1275.
http://dx.doi.org/10.1038/nbt.1502
[61] Nishikawa, S., Goldstein, R.A. and Nierras, C.R. (2008) The promise of human induced pluripotent stem cells for research and therapy. Nature Reviews Molecular Cell Biology, 9, 725-729.
http://dx.doi.org/10.1038/nrm2466
[62] Park, I.H., Lerou, P.H., Zhao, R., Huo, H. and Daley, G.Q. (2008) Generation of humaninduced pluripotent stem cells. Nature Protocols, 3, 1180-1186.
http://dx.doi.org/10.1038/nprot.2008.92
[63] Tatard, V.M., Venier-Julienne, M.C., Saulnier, P., Prechter, E., Benoit, J.P., Menei, P. and Montero-Menei, C.N. (2005) Pharmacologically active microcarriers: A tool for cell therapy. Biomaterials, 26, 3727-3737.
http://dx.doi.org/10.1016/j.biomaterials.2004.09.042
[64] Prakash, S., Khan, A. and Paul, A. (2010) Nanoscaffold based stem cell regeneration therapy: Recent advancement and future potential. Expert Opinion on Biological Therapy, 10, 1649-1661.
http://dx.doi.org/10.1517/14712598.2010.528387
[65] Madonna, R. and De Caterina, R. (2011) Stem cells and growth factor delivery systems for cardiovascular disease. Journal of Biotechnology, 154, 291-297.
http://dx.doi.org/10.1016/j.jbiotec.2011.05.014
[66] Trounson, A., DeWitt, N.D. and Feigal, E.G. (2012) The Alpha Stem Cell Clinic: A model for evaluating and delivering stem cell-based therapies. Stem Cells Translational Medicine, 1, 9-14.
http://dx.doi.org/10.5966/sctm.2011-0027

  
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