Clinical and Health Affairs
Regenerative Medicine
A Reality of Stem Cell Technology
By Andre Terzic, M.D., Ph.D., Brooks S. Edwards, M.D., Katherine C. McKee, and Timothy J. Nelson, M.D., Ph.D.
■ Regenerative medicine aims to restore homeostasis through a broad spectrum of strategies ranging from transplantation of donor organs to augmentation of innate healing processes. Its first clinical application emerged five decades ago when bone marrow-derived stem cells were used to replace defective progenitor cells. Since then, a variety of technological advances have expanded its scope. Most recently, the advent of natural or bioengineered stem cell products for tissue repair has inspired hope that the toughest obstacles in transplant medicine—the shortage of organs and organ rejection—might be overcome. This article describes the evolution of regenerative medicine and some of the ways it is being used in research and clinical practice.
Transplant medicine has laid the foundation for the emerging field of regenerative medicine, as the central aim of transplantation is replacing defective tissue with functional tissue in order to heal patients with end-stage disease.1 Over the years, tissue and solid-organ transplantation have been used to treat patients with otherwise incurable diseases such as leukemia, cirrhosis, end-stage kidney disease, and cardiopulmonary failure.2 Although transplantation has proved to be extraordinarily successful for some patients, the limited availability of appropriate organs and tissues and the problem of rejection have created a need for new strategies to meet the demands.3 Regenerative medicine offers potential solutions to these critical challenges.
Once, stem cell research and solid organ transplantation were separate endeavors. Materials science and developmental biology have bridged those fields, creating the new field of regenerative medicine. The initial application of regenerative medicine occurred five decades ago when hematologists began using bone marrow-derived stem cells as a replacement for defective progenitor cells. Advances in cell, tissue, and organ engineering have since led to new possibilities.4,5 Today, a variety of regenerative applications are being used and tested. In many cases, standards of care and best practices have yet to be established for cell-based regenerative therapies; however, clinical trials conducted by reputable institutions are actively enrolling patients in order to accelerate the translation of these promising applications. Regrettably, unproven therapies also are being marketed directly to patients, who may need to travel to other countries to get them.
As a result of the increased awareness on the part of patients, clinicians increasingly find themselves having to provide opinions about these therapies, some of which may be harmful or inappropriate for certain conditions. Thus, primary care providers and other specialists need to be informed about the state of regenerative medicine and emerging therapies that hold promise as well as those that are merely hype.
A Stem Cell Primer
Stem cells are the building blocks of regenerative medicine. As research on stem cells progresses, new information is becoming available daily regarding breakthrough technologies that will have an impact on our ability to translate stem cell science into clinical products and services. Regenerative medicine largely draws from four stem cell
Mayo Clinic’s Regenerative Medicine Consult Service
Patients and their family members increasingly ask about the potential of regenerative medicine applications. To address this growing interest, Mayo Clinic has created a clinical service within its Transplant Center that provides guidance for patients and families considering stem cell-based protocols.
The Mayo Clinic Regenerative Medicine Consult Service is designed to educate patients about the risks and potential benefits of clinical trials involving stem cell therapy and to dispel myths about misleading claims about products or services sold on the open market. Physicians from the service also can connect patients with clinical trials and stem cell-based protocols, if appropriate. The service is available at the request of providers. For an appointment, contact the Regenerative Medicine Consult Service at 507/538-3270.
|
populations that function as tissue progenitors: embryonic stem cells, perinatal stem cells, adult stem cells, and bioengineered stem cells.
6 Each cell type has unique properties.
As their name implies, embryonic stem cells are stem cells derived from embryos that are the product of in vitro fertilization. These cells are pluripotent, meaning they can differentiate into all adult tissue types. Because of their differentiation capacity, embryonic stem cells are suitable for deriving tissues that are difficult to obtain such as retinal pigment epithelial cells lost in macular degeneration and other tissues damaged by disease. However, the ethical and social considerations surrounding the use of embryonic stem cells continue to foster debate and challenge our legal system.
Perinatal stem cells are derived from umbilical cord blood. Although it is frequently discarded after birth, umbilical cord blood can be stored in private facilities or in public biobanks for later use in treating diseases such as leukemia. Perinatal stem cells are considered multipotent—that is, they can differentiate into many but not all tissue types.
Adult stem cells are present in many tissues including bone marrow, adipose tissue, and circulating blood. Unlike embryonic stem cells, adult stem cells are considered multipotent or oligopotent because their differentiation potential is restricted. This class of stem cells is most commonly used for treating lymphoma, leukemia, or autoimmune diseases that require cytotoxic treatments followed by rescue of the hematopoietic lineages and immune system. Currently, mesenchymal cells, which are derived from adult sources such as bone marrow or adipose tissue, are favored in clinical applications because they are widely accessible and because they have multipotent differentiation capacity, favorable growth characteristics, and an encouraging safety/efficacy record in clinical transplantation.7
Bioengineered stem cells are a recent development. Scientists have been able to create induced pluripotent stem (iPS) cells using ordinary tissues such as the fibroblasts obtained from a dermal biopsy. With reprogramming or by applying genes typically expressed in embryonic tissues, adult fibroblasts can undergo a dramatic transformation and be reset to look and feel like embryonic stem cells. In other words, bioengineered iPS cells acquire the traits of pluripotent stem cells and the ability to differentiate into all types of tissue. These cells could be the game changer with regard to organ and tissue transplantation, as their use could offer a virtually unlimited renewable pool of tissues derived from the patient’s own cells, eliminating the problems of donor shortages and rejection. They also offer a way around the ethical and political concerns associated with embryonic stem cell technology. Since the advent of iPS cell technology, bioengineered stem cells have become a source for progenitor derivation, tissue-specific differentiation, and repair in preclinical studies.8,9
Clinical trials using adult stem cells to treat diverse conditions have established that this approach is safe and practical; early results of treatments for ischemic heart disease show promise.10 Therapies using umbilical cord blood stem cells, embryonic stem cells, and tissue-specific progenitors derived from adult stem cell populations are being developed for early-phase clinical studies.11
Emerging Applications for Regenerative Medicine
A number of developments are enabling investigators to envision new therapies and applications. The advent of bioengineered pluripotent stem cells is particularly significant.12 The ability to re-create pluripotent stem cells from ordinary somatic tissues such as blood or dermal fibroblasts makes it possible to create therapies that might one day eliminate the need for allogeneic transplantation. Tissues that have been created using iPS technology include dopaminergic neurons (to replace those damaged by Parkinson disease), beta cells from the pancreas (diabetes), cardiomyocytes (ischemic heart disease), retinal pigment epithelial cells (macular degeneration or Stargardt disease), red blood cells (hemophilia and sickle cell disease), and hepatocytes (chronic liver diseases). At Mayo Clinic, we have pioneered the use of bioengineered iPS cells for treating cardiovascular diseases in preclinical studies.13 We are now applying this technology to ischemic and nonischemic cardiomyopathy and congenital heart diseases.14 Furthermore, the ability to program human iPS cells into glucose-responsive insulin-secreting progeny has been recently refined.15
Questions Patients Frequently Ask
- Are there stem cell therapies or clinical trials that can treat my condition?
- When will stem cell therapies be used to treat my condition?
- Where are they using regenerative medicine to treat my condition?
- Is a specific stem cell service safe for my condition?
- What are the differences between the various forms of stem cells?
- Are all stem cells derived from embryonic tissues?
The following websites can help you provide answers to some of these questions:
|
Advances in materials science are opening new avenues of research in regenerative medicine. Matrices produced from natural or synthetic sources now provide platforms for growing tissue grafts and even engineering organs.16 In fact, preclinical studies have demonstrated that it is possible to decellularize organs and leave behind only the extra-cellular matrix backbone. This natural three-dimensional scaffold provides a framework for progenitor cells to engraft and recreate the structure and function of organs such as the myocardium.16 The ultimate goal of this work is to one day build replacement organs.
Such breakthroughs are setting the stage for new clinical applications. One of the most innovative ones was a whole-organ replacement of the upper airway.17 Using a decellularized scaffold from a cadaver trachea, a team of clinicians, scientists, and engineers repopulated the matrix with mesenchymal stem cells derived from the patient’s bone marrow. After months of reconstruction in the laboratory, the trachea was surgically transplanted in the patient without requiring immunosuppression.
In addition to such therapeutic applications, regenerative medicine may also lead to better methods of testing pharmaceuticals. As part of safety testing, all new pharmaceuticals must be evaluated for their toxicity. With the ability to produce human tissues using bioengineering processes, we may be able to test drugs in the laboratory before they are administered to the patient. For example, scientists are now testing cardiotoxicity of certain drugs using bioengineered cardiomyocytes.18
Regenerative medicine also may help identify patients within the transplant population who will have more aggressive disease or who may be at risk for complications following organ transplantation. In other words, we may be able to use bioengineered constructs in the lab made from tissue from the patient’s own body to predict such things as the long-term effect of exposure to immunosuppression medications. This ability to identify deficiencies in the tissue-renewal process also may be useful for creating individualized therapies for a variety of other diseases as well.
Therapeutic uses are the ultimate goal of regenerative medicine. First-generation technologies are currently being studied with the aim of defining safety profiles of biologic agents while determining their efficacy in order to guide next-generation applications. This work will no doubt expand the number and type of patients who can be safely managed with tissue or organ transplantation. Autologous and allogeneic stem cells obtained from adipose tissue, bone marrow or peripheral blood, or bioengineered stem cells are already being used in applications designed to improve tissue healing in patients with ischemic heart disease,19 liver disease,20 neurological disorders,21 endocrinopathy,22 progressive lung conditions,23 and dermal wounds.24 Mayo Clinic physicians and scientists are developing procedures and infrastructure to support and accelerate clinical trials related to human stem cell therapies.25-27
Prospects for the Future Regenerative medicine is redefining the future for patients with end-stage organ disease.28 It promises better, safer treatment at earlier stages and the possibility of cure rather than palliation of symptoms. Because its applications cross all medical disciplines, realizing the full potential of regenerative medicine will require collaboration among experts from multiple fields.
Clinical services may need to be restructured as new products and services become available, and as those products and services do more than treat specific organs or diseases. In addition, hospitals and clinics may need to dedicate resources to the field in order to efficiently navigate the regulatory processes for investigational new drug applications, FDA reporting, and monitoring the safety of their clinical activities.29
In addition, they may need personnel dedicated to dealing with the growing number of patients inquiring about new treatments and services (see “Mayo Clinic’s Regenerative Medicine Consult Service”). All physicians will need to know about advances in regenerative medicine and stay well-informed of developments in bench research and clinical trials as well as the limitations of therapies. How the medical community responds may be the key to whether regenerative medicine fully realizes its potential for returning patients to health. MM
Timothy Nelson is the E. Rolland Dickson scholar in transplant medicine at Mayo Clinic and director of regenerative medicine consult service in the William J. von Liebig Transplant Center; Brooks Edwards is director of the Mayo Clinic Transplant Center and deputy director Mayo Clinic Center for Regenerative Medicine; Katherine McKee is transplant center operations manager; and Andre Terzic is director of the Mayo Clinic Center for Regenerative Medicine.
References
1. Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: The “R3” regenerative medicine paradigm. Clin Transl Sci. 2008;1(2):168-71.
2. Lechler RI, Sykes M, Thomson AW, Turka LA. Organ transplantation--how much of the promise has been realized? Nat Med. 2005;11(6):605-13.
3. Salim A, Martin M, Brown C, Rhee P, Demetriades D, Belzberg H. The effect of a protocol of aggressive donor management: implications for the national organ donor shortage. J Trauma. 2006;61(2):429-33.
4. Daley GQ, Scadden DT. Prospects for stem cell-based therapy. Cell. 2008;132(4):544-8.
5. Surani MA, McLaren A. Stem cells: a new route to rejuvenation. Nature. 2006;443(7109):284-5.
6. Nelson TJ, Behfar A, Yamada S, Martinez-Fernandez A, Terzic A. Stem cell platforms for regenerative medicine. Clin Transl Sci. 2009;2(3):222-7.
7. Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair— current views. Stem Cells. 2007;25(11):2896-902.
8. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4): 663-76.
9. Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell. 2007;1(1):39-49.
10. Bartunek J, Vanderheyden M, Hill J, Terzic A. Cells as biologics for cardiac repair in ischaemic heart failure. Heart. 2010;96(10):792-800.
11. van de Ven C, Collins D, Bradley MB, Morris E, Cairo MS. The potential of umbilical cord blood multipotent stem cells for nonhematopoietic tissue and cell regeneration. Exp Hematol. 2007;35(12):1753-65.
12. Nelson TJ, Terzic A. Induced pluripotent stem cells: an emerging theranostics platform. Clin Pharmacol Ther. (23 March 2011) doi:10.1038/clpt.2011.9.
13. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A. Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation. 2009;120(5):408-16.
14. Nelson TJ, Martinez-Fernandez A, Terzic A. Induced pluripotent stem cells: developmental biology to regenerative medicine. Nat Rev Cardiol. 2010;7(12): 700-10.
15. Thatava T, Nelson TJ, Edukulla R, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther. 2011;18(3):283-93.
16. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14(2):213-21.
17. Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet. 2008;372(9655):2023-30.
18. Inoue H, Yamanaka S. The use of induced pluripotent stem cells in drug development. Clin Pharmacol Ther. (23 March 2011) doi:10.1038/clpt.2011.38.
19. Gersh BJ, Simari RD, Behfar A, Terzic CM, Terzic A. Cardiac cell repair therapy: a clinical perspective. Mayo Clin Proc. 2009;84(10):876-92.
20. McKenzie TJ, Lillegard JB, Nyberg SL. Artificial and bioartificial liver support. Semin Liver Dis. 2008 May;28(2):210-7.
21. Martino G, Franklin RJ, Van Evercooren AB, Kerr DA; Stem Cells in Multiple Sclerosis (STEMS) Consensus Group. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-55.
22. Domínguez-Bendala J, Inverardi L, Ricordi C. Stem cell-derived islet cells for transplantation. Curr Opin Organ Transplant. 2010 Dec 9. [Epub ahead of print].
23. Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res. 2010;156(3):188-205.
24. Wu SC, Marston W, Armstrong DG. Wound care: the role of advanced wound healing technologies. J Vasc Surg. 2010;52(3 Suppl):59S-66S.
25. Dietz AB, Padley DJ, Gastineau DA. Infrastructure development for human cell therapy translation. Clin Pharmacol Ther. 2007;82(3):320-4.
26. Simari RD, Moyé LA, Skarlatos SI, et al. Development of a network to test strategies in cardiovascular cell delivery: the NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN). J Cardiovasc Transl Res. 2010;3(1):30-6.
27. Behfar A, Yamada S, Crespo-Diaz R, et al. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol. 2010;56(9):721-34.
28. Terzic A, Nelson TJ. Regenerative medicine advancing health care 2020. J Am Coll Cardiol. 2010;55(20):2254-7.
29. Dolgin E. Survey details stem cell clinics ahead of regulatory approval. Nat Med. 2010;16(5):495.