- Email: [email protected]
Stem cell based therapy—where are we going?
Comment
3
4
5
Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: the randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. Circulation 2008; 118: 49–57. Thiele H, Wöhrle J, Hambrecht R, et al. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST elevation myocardial infarction: a randomised trial. Lancet 2012; published online Feb 21. DOI:10.1016/S0140-6736(11)61872-2. Shimada YJ, Nakra NC, Fox JT, Kanei Y. Meta-analysis of prospective randomized controlled trials comparing intracoronary versus intravenous abciximab in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol 2011; published online Dec 7. DOI:10.1016/j.amjcard.2011.10.016.
6
7
8
Friedland S, Eisenberg MJ, Shimony A. Meta-analysis of randomized controlled trials of intracoronary versus intravenous administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention for acute coronary syndrome. Am J Cardiol 2011; 108: 1244–51. De Luca G, Navarese E, Marino P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur Heart J 2009; 30: 2705–13. Desch S, Siegemund A, Scholz U, et al. Platelet inhibition and GP IIb/IIIa receptor occupancy by intracoronary versus intravenous bolus administration of abciximab in patients with ST-elevation myocardial infarction. Clin Res Cardiol 2011; published online Oct 21. DOI:10.1007/s00392-011-0372-6.
Cell based regenerative therapy with stem cells from bone marrow has been reported widely and used for more than 50 years.1 However, use of stem cells for regenerative medicine has only recently captured the imagination of the public, with media attention contributing to rising expectations of clinical benefit. Optimism that stem cells will provide a virtually unlimited source of selected cell types for future cell therapies, as well as for drug screening and development, has resulted in substantial progress in stem cell biology in the past decade. Heart failure—one of the leading causes of morbidity and mortality in developed and developing countries with few treatment options—was the most important testing ground for stem cell based therapies. Clinical trials have so far focused on three heart conditions: acute myocardial infarction, chronic heart failure, and dilated cardiomyopathy. The trials have suggested that stem cell based therapies are safe, but clinical efficacy has yet to be seen.2,3 Because of the complexity of the task, an interdisciplinary team from academia and the private sector is most likely to succeed. Favourable clinical outcomes would not, however, mean that the public will see benefits immediately. Numerous legal and practical issues need to be resolved before such therapy could be applied to patients cost-effectively and consistent with present treatment approaches. For example, although the use of advanced delivery equipment such as the NOGA XP Cardiac Navigation System might improve homing and subsequent engraftment of transplanted cells to the damaged heart tissue, it would augment stem cell therapy costs and limit the number of delivery facilities, making the treatment less affordable.4 Many practitioners worldwide have joined this growing movement, and injected various types of stem cells into www.thelancet.com Vol 379 March 10, 2012
damaged organs of patients with different debilitating diseases, with the hope that healthy cells would repopulate ailing tissue and partly or fully restore function. Attempts ranged from well-designed, multicentre, controlled trials that were scrutinised and approved by governmental agencies to efforts by private-sector entities less constrained by the demands of scientific rigour.5 Despite tremendous enthusiasm the results were generally inconclusive. The absence of systematic approaches and consistency made meta-analyses difficult, if not impossible. Therefore, the transplantation of stem cells from bone marrow, umbilical cord blood, or peripheral blood for treatment of haemopoietic diseases is probably the only safe and controlled stem cell based therapy in use today Nevertheless, striking progress in basic research towards stem cell regenerative therapy has been made and new trends have emerged. Mobilisation of endogenous progenitor cells has been used widely as a treatment strategy in haematology for many years. Identification of resident stem cells in almost every solid organ in the body triggered a flurry of research towards enhancement of endogenous regenerative activity, especially in the specialties of heart and brain repair.2,6 The notion that successful stem cell therapy relies more on the paracrine effects of transplanted cells than on transdifferentiation and functional replacement of damaged cells opened new avenues for treatment approaches.2,7 Native or genetically modified stem cells, encapsulated in semipermeable ultrathin membranes, can be used as vehicles to deliver desired secreted soluble factors or other bioactive molecules directly to the site of injury and create a supportive healing microenvironment.8 Studies with insulin-producing β-cells showed that advanced nanocoating techniques, such as polysaccharide
Dusko Ilic
Stem cell based therapy—where are we going?
See Comment page 870 See Series pages 933 and 943
877
Comment
multilayer nanoencapsulation, support both long-term cell viability and metabolic functionality of encapsulated cells and simultaneously abolish the need for immunosuppressive therapy.9 Therefore, off-the-shelf cell based products could possibly be developed to allow specific tissue repair or disease treatments. Preservation of the native three-dimensional ultrastructure, surface topology, and composition of extracellular matrix will probably contribute to the success of biological scaffolds derived from decellularised organs.10,11 Distinct biochemical and physical forces, which are unique for every tissue, dictate the spatial organisation and chemical composition of the extracellular matrix. Stem cells seeded on such a scaffold respond to diverse cues coming from the extracellular matrix via various adhesion structures and adapt to the specific microenvironment by adoption of different differentiation pathways and specialisation for different functions. Although several questions are unresolved, the promise of an off-the-shelf scaffold that can be repopulated with autologous stem cells expanded in vitro seems much closer than one could have hoped for even a few years ago.12 Changing the fate of differentiated human somatic cells from one to another cell type, known as direct reprogramming, or to induced pluripotent stem (iPS) cells, which have properties similar to human embryonic stem (hES) cells, could open a new era in areas of regenerative and personalised medicine.13 Directly reprogrammed and iPS cells could circumvent the absence of matching tissues for organ transplantation and need for life-long treatment with immunosuppressants. No consensus exists for the optimum protocols for deriving the most reliable and the safest iPS cells and, before reprogramming technology could be applied in translational medicine, a number of technical issues should be resolved.14 However, prohibitive costs, rather than safety and technical issues, will probably restrict their use in therapy in the foreseeable future. In a controlled, consistent, good manufacturing practice environment with trained staff, at present, only hES cells can be straightforwardly and inexpensively expanded indefinitely, keeping their differentiation potential unaltered. Therefore, in the long term hES cells seem to be the best human stem cell model for capital investment at present.4,15 Indeed, preliminary data from a clinical trial16 of hES cell based therapy of Stargardt’s macular dystrophy and dry age-related macular degeneration showed not only safety, 878
but also some visual improvement, in the first two treated patients. If early applications of stem cell based therapies, especially hES cells, fail or cause unforeseen issues, the public will need reassurance that it is not the end of an era. Recently, the US company Geron caused a considerable stir when it announced the closure of its hES cell based clinical trial in spinal cord injury because of a lack of investment and support.17 To keep hope alive, governments and the private sector will have to show confidence in stem cell research by continuous investment in a new generation of researchers who will move science forward and translate discoveries into reliable clinical outcomes. *Dusko Ilic, Julia Polak Embryonic Stem Cell Laboratories, Guy’s Assisted Conception Unit, Division of Women’s Health, King’s College Medical School, London SE1 9RT, UK (DI); and Faculty of Medicine, Regenerative Medicine, Department of Chemical Engineering, Imperial College, South Kensington Campus, London, UK (JP) [email protected] We declare that we have no conflicts of interest. 1
2 3 4
5
6. 7 8
9
10 11 12
13
14 15 16 17
Mathe G, Jammet H, Pendic B, et al. Transfusions and grafts of homologous bone marrow in humans after accidental dosage irradiation. Rev Fr Etud Clin Biol 1959; 4: 226–38. Ptaszek LM, Mansour M, Ruskin JN, Chien KR. Towards regenerative therapy for cardiac disease. Lancet 2012; 379: 933–42. Mozid AM, Arnous S, Sammut EC, Mathur A. Stem cell therapy for heart diseases. Br Med Bull 2011; 98: 143–59. Salaway T, Ilic D. Logistics of stem cell isolation, preparation and delivery for heart repair: concerns of clinicians, manufacturers, investors and public health. Regen Med 2008; 3: 83–91. Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell 2008; 3: 591–94. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132: 645–60. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med 2010; 5: 121–43. Zhi ZL, Lio B, Jones PM, Pickup JC. Polysaccharide multilayer nanoencapsulation of insulin-producing beta-cells grown as pseudoislets for potential cellular delivery of insulin. Biomacromolecules 2010; 11: 610–16. Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C. Live encapsulated porcine islets from a type 1 diabetic patient 9·5 yr after xenotransplantation. Xenotransplantation 2007; 14: 157–61. Badylak SF, Weiss DJ, Caplan A, Macchiarini P. Engineered whole organs and complex tissues. Lancet 2012; 379: 943–52. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization process. Biomaterials 2011; 32: 3233–43. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Burridge PW, Keller G, Gold JD, Wu JC. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 2012; 10: 16–28. Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 2012; 481: 295–305. Brindley DA, Reeve BC, Sahlman WA, et al. The impact of market volatility on the cell therapy industry. Cell Stem Cell 2011; 9: 397–401. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379: 713–20. Brindley D, Mason C. Human embryonic stem cell therapy in the post-Geron era. Regen Med 2012; 7: 17–18.
www.thelancet.com Vol 379 March 10, 2012
3
4
5
Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: the randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. Circulation 2008; 118: 49–57. Thiele H, Wöhrle J, Hambrecht R, et al. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST elevation myocardial infarction: a randomised trial. Lancet 2012; published online Feb 21. DOI:10.1016/S0140-6736(11)61872-2. Shimada YJ, Nakra NC, Fox JT, Kanei Y. Meta-analysis of prospective randomized controlled trials comparing intracoronary versus intravenous abciximab in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol 2011; published online Dec 7. DOI:10.1016/j.amjcard.2011.10.016.
6
7
8
Friedland S, Eisenberg MJ, Shimony A. Meta-analysis of randomized controlled trials of intracoronary versus intravenous administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention for acute coronary syndrome. Am J Cardiol 2011; 108: 1244–51. De Luca G, Navarese E, Marino P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur Heart J 2009; 30: 2705–13. Desch S, Siegemund A, Scholz U, et al. Platelet inhibition and GP IIb/IIIa receptor occupancy by intracoronary versus intravenous bolus administration of abciximab in patients with ST-elevation myocardial infarction. Clin Res Cardiol 2011; published online Oct 21. DOI:10.1007/s00392-011-0372-6.
Cell based regenerative therapy with stem cells from bone marrow has been reported widely and used for more than 50 years.1 However, use of stem cells for regenerative medicine has only recently captured the imagination of the public, with media attention contributing to rising expectations of clinical benefit. Optimism that stem cells will provide a virtually unlimited source of selected cell types for future cell therapies, as well as for drug screening and development, has resulted in substantial progress in stem cell biology in the past decade. Heart failure—one of the leading causes of morbidity and mortality in developed and developing countries with few treatment options—was the most important testing ground for stem cell based therapies. Clinical trials have so far focused on three heart conditions: acute myocardial infarction, chronic heart failure, and dilated cardiomyopathy. The trials have suggested that stem cell based therapies are safe, but clinical efficacy has yet to be seen.2,3 Because of the complexity of the task, an interdisciplinary team from academia and the private sector is most likely to succeed. Favourable clinical outcomes would not, however, mean that the public will see benefits immediately. Numerous legal and practical issues need to be resolved before such therapy could be applied to patients cost-effectively and consistent with present treatment approaches. For example, although the use of advanced delivery equipment such as the NOGA XP Cardiac Navigation System might improve homing and subsequent engraftment of transplanted cells to the damaged heart tissue, it would augment stem cell therapy costs and limit the number of delivery facilities, making the treatment less affordable.4 Many practitioners worldwide have joined this growing movement, and injected various types of stem cells into www.thelancet.com Vol 379 March 10, 2012
damaged organs of patients with different debilitating diseases, with the hope that healthy cells would repopulate ailing tissue and partly or fully restore function. Attempts ranged from well-designed, multicentre, controlled trials that were scrutinised and approved by governmental agencies to efforts by private-sector entities less constrained by the demands of scientific rigour.5 Despite tremendous enthusiasm the results were generally inconclusive. The absence of systematic approaches and consistency made meta-analyses difficult, if not impossible. Therefore, the transplantation of stem cells from bone marrow, umbilical cord blood, or peripheral blood for treatment of haemopoietic diseases is probably the only safe and controlled stem cell based therapy in use today Nevertheless, striking progress in basic research towards stem cell regenerative therapy has been made and new trends have emerged. Mobilisation of endogenous progenitor cells has been used widely as a treatment strategy in haematology for many years. Identification of resident stem cells in almost every solid organ in the body triggered a flurry of research towards enhancement of endogenous regenerative activity, especially in the specialties of heart and brain repair.2,6 The notion that successful stem cell therapy relies more on the paracrine effects of transplanted cells than on transdifferentiation and functional replacement of damaged cells opened new avenues for treatment approaches.2,7 Native or genetically modified stem cells, encapsulated in semipermeable ultrathin membranes, can be used as vehicles to deliver desired secreted soluble factors or other bioactive molecules directly to the site of injury and create a supportive healing microenvironment.8 Studies with insulin-producing β-cells showed that advanced nanocoating techniques, such as polysaccharide
Dusko Ilic
Stem cell based therapy—where are we going?
See Comment page 870 See Series pages 933 and 943
877
Comment
multilayer nanoencapsulation, support both long-term cell viability and metabolic functionality of encapsulated cells and simultaneously abolish the need for immunosuppressive therapy.9 Therefore, off-the-shelf cell based products could possibly be developed to allow specific tissue repair or disease treatments. Preservation of the native three-dimensional ultrastructure, surface topology, and composition of extracellular matrix will probably contribute to the success of biological scaffolds derived from decellularised organs.10,11 Distinct biochemical and physical forces, which are unique for every tissue, dictate the spatial organisation and chemical composition of the extracellular matrix. Stem cells seeded on such a scaffold respond to diverse cues coming from the extracellular matrix via various adhesion structures and adapt to the specific microenvironment by adoption of different differentiation pathways and specialisation for different functions. Although several questions are unresolved, the promise of an off-the-shelf scaffold that can be repopulated with autologous stem cells expanded in vitro seems much closer than one could have hoped for even a few years ago.12 Changing the fate of differentiated human somatic cells from one to another cell type, known as direct reprogramming, or to induced pluripotent stem (iPS) cells, which have properties similar to human embryonic stem (hES) cells, could open a new era in areas of regenerative and personalised medicine.13 Directly reprogrammed and iPS cells could circumvent the absence of matching tissues for organ transplantation and need for life-long treatment with immunosuppressants. No consensus exists for the optimum protocols for deriving the most reliable and the safest iPS cells and, before reprogramming technology could be applied in translational medicine, a number of technical issues should be resolved.14 However, prohibitive costs, rather than safety and technical issues, will probably restrict their use in therapy in the foreseeable future. In a controlled, consistent, good manufacturing practice environment with trained staff, at present, only hES cells can be straightforwardly and inexpensively expanded indefinitely, keeping their differentiation potential unaltered. Therefore, in the long term hES cells seem to be the best human stem cell model for capital investment at present.4,15 Indeed, preliminary data from a clinical trial16 of hES cell based therapy of Stargardt’s macular dystrophy and dry age-related macular degeneration showed not only safety, 878
but also some visual improvement, in the first two treated patients. If early applications of stem cell based therapies, especially hES cells, fail or cause unforeseen issues, the public will need reassurance that it is not the end of an era. Recently, the US company Geron caused a considerable stir when it announced the closure of its hES cell based clinical trial in spinal cord injury because of a lack of investment and support.17 To keep hope alive, governments and the private sector will have to show confidence in stem cell research by continuous investment in a new generation of researchers who will move science forward and translate discoveries into reliable clinical outcomes. *Dusko Ilic, Julia Polak Embryonic Stem Cell Laboratories, Guy’s Assisted Conception Unit, Division of Women’s Health, King’s College Medical School, London SE1 9RT, UK (DI); and Faculty of Medicine, Regenerative Medicine, Department of Chemical Engineering, Imperial College, South Kensington Campus, London, UK (JP) [email protected] We declare that we have no conflicts of interest. 1
2 3 4
5
6. 7 8
9
10 11 12
13
14 15 16 17
Mathe G, Jammet H, Pendic B, et al. Transfusions and grafts of homologous bone marrow in humans after accidental dosage irradiation. Rev Fr Etud Clin Biol 1959; 4: 226–38. Ptaszek LM, Mansour M, Ruskin JN, Chien KR. Towards regenerative therapy for cardiac disease. Lancet 2012; 379: 933–42. Mozid AM, Arnous S, Sammut EC, Mathur A. Stem cell therapy for heart diseases. Br Med Bull 2011; 98: 143–59. Salaway T, Ilic D. Logistics of stem cell isolation, preparation and delivery for heart repair: concerns of clinicians, manufacturers, investors and public health. Regen Med 2008; 3: 83–91. Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell 2008; 3: 591–94. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132: 645–60. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med 2010; 5: 121–43. Zhi ZL, Lio B, Jones PM, Pickup JC. Polysaccharide multilayer nanoencapsulation of insulin-producing beta-cells grown as pseudoislets for potential cellular delivery of insulin. Biomacromolecules 2010; 11: 610–16. Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C. Live encapsulated porcine islets from a type 1 diabetic patient 9·5 yr after xenotransplantation. Xenotransplantation 2007; 14: 157–61. Badylak SF, Weiss DJ, Caplan A, Macchiarini P. Engineered whole organs and complex tissues. Lancet 2012; 379: 943–52. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization process. Biomaterials 2011; 32: 3233–43. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Burridge PW, Keller G, Gold JD, Wu JC. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 2012; 10: 16–28. Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 2012; 481: 295–305. Brindley DA, Reeve BC, Sahlman WA, et al. The impact of market volatility on the cell therapy industry. Cell Stem Cell 2011; 9: 397–401. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379: 713–20. Brindley D, Mason C. Human embryonic stem cell therapy in the post-Geron era. Regen Med 2012; 7: 17–18.
www.thelancet.com Vol 379 March 10, 2012