Anthony Atala, MD Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina. Sean Murphy, PhD Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina.

Author Reading at jama.com

Corresponding Author: Anthony Atala, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC 27106 (aatala @wakehealth.edu).

Regenerative Medicine The Culture of Organs, a book published in 1938 by Nobel Laureate Alexis Carrel and well-known aviator Charles Lindbergh, described how organs could be kept “alive” in culture for months, with the intent to reuse them. Decades later, regenerative medicine, a field of science that aims to restore or establish normal function by replacing or regenerating human cells, tissues, and organs affected by disease, is becoming a reality. The field is a progression of previous efforts to restore function, ranging from prosthetics to organ transplants. Advances in cell biology, biomaterial science, and biological molecule discovery have led to new options for cellular therapies, engineered tissues and organs, and new strategies to stimulate endogenous repair and regeneration.

Cell Therapy The ability to understand and control human cell function has been a central focus of regenerative medicine. The therapeutic application of cells dates back to the pioneering work of bone marrow transplants in the 1950s. The clinical use of bone marrow–derived stem cells to reconstitute the hematopoietic system as a treatment for patients with cancers and other disorders of the blood and immune system provided the foundation for current cell therapy strategies. The isolation and characterization of human embryonic stem cells demonstrated the potential of stem cell therapy. However, limitations regarding the clinical translation of these cell types, as well as an improved understanding of stemness, the process by which stem cells form and differentiate, facilitated the generation of induced pluripotent stem cells through somatic cell reprogramming.1 A variety of techniques have been developed to generate induced pluripotent stem cells that are functionally similar to embryonic stem cells. The ability to generate large numbers of functional cell types through the process of differentiation enabled the therapeutic application of pluripotent stem cells, such as the use of embryonic stem cell–derived retinal pigmented epithelial cells to treat macular dystrophy and agerelated macular degeneration.2 Rapid advances have led to a recent trial using integration-free, autologous induced pluripotent stem cells to treat age-related macular degeneration in Japan. Stem cell populations have also been identified in perinatal and adult tissues, including the amniotic fluid, placenta, bone marrow, and blood vessels. Although many of the initial studies focused on the multipotentiality of these cells, several also have immunemodulatory functions. Allogeneic human mesenchymal stem cell therapy is the first product to be approved in North America (Canada), and has recently proven successful in clincal trials for treating graft-vs-host disease.


Tissue Engineering Tissues and organs comprise multiple functional and supporting cell types, and accurate replication at both the cellular and macro level is required for normal function of engineered tissues. The fabrication of tissues has generally been achieved through the encapsulation or seeding of cells within biodegradable materials. Most of the biomaterials used in tissue-engineering applications are either synthetic or naturally derived. The biomaterials used in tissue-engineered constructs have been largely dictated by their physical properties, such as stiffness, flexibility, and porosity, as well as biological properties such as bioactivity and degradation timelines. New developments in material sciences have facilitated the ability to tailor the material properties to meet the requirements of the tissue-engineered construct. For example, the design of biomimetic and peptide-conjugated synthetic materials has significantly improved their cellular compatibility and bioactivity, whereas the chemical functionalization of “natural” materials has produced materials with adaptable mechanical properties, degradation times, and cross-linking options.3 The design and fabrication of tissue-engineered constructs have been greatly influenced by modern manufacturing techniques. As the complexity of the native tissues increases, from flat structures such as skin, to tubular structures such as blood vessels, to hollow nontubular organs such as the bladder, and to solid organs such as the heart, the complexity of manufacturing also increases. For the nonsolid tissues, fabrication can be achieved using electrospinning, casting, or other traditional techniques, and tissue-engineered skin, cartilage, tracheas, blood vessels, urethras, bladders, and vaginas have been implanted in patients using these strategies. Complex solid organs require newer approaches to replicate the complex 3-dimensional structures. The use of decellularized solid organs that can be reseeded with the patient’s own cells has been proposed, although preserving patency in the end capillaries remains a challenge for transferring these technologies to patients. The rapid adoption of bioprinting has resulted in the development of custom-made hardware capable of precise layer-by-layer organization of biological materials, biochemicals, and living cells into complex 3-dimensional structures. There are various design strategies used for 3-dimensional bioprinting, such as biomimicry, autonomous self-assembly, and mini-tissue building blocks.4 While 3-dimensional bioprinting is still a relatively recent approach to engineering tissues and organs, successful application for the fabrication of tracheal splints, skin, bone, cartilage, vascular grafts, and heart tissue demonstrates the wide application of this technique. (Reprinted) JAMA April 14, 2015 Volume 313, Number 14

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Opinion Viewpoint

Regenerative Pharmacology Strategies have been developed to induce endogenous stem cells. This ability was first demonstrated in the hematopoietic system, whereby stem cells are mobilized into the peripheral blood by stimulation with cytokines, small molecules, or both, resulting in improved engraftment. Chemical approaches to stimulate other tissuespecific stem cells also show promise, like the development of small molecule-driven cell renewal and induction into a differentiated phenotype.5 Genetic strategies have been developed to induce terminally differentiated somatic cells directly into a desired functional phenotype. One example of this approach is the virus-mediated expression of a trio of cardiac-specific transcription factors in resident cardiac fibroblasts in vivo, resulting in the reprogramming of these cells directly into cardiomyocytelike cells with ventricular action potentials, electrical coupling, and beating upon electrical stimulation.6 This approach has also been successful in the pancreas, with in vivo virus-mediated expression of specific transcription factors in differentiated pancreatic exocrine cells resulting in the reprogramming of these cells into pancreatic β-like cells. Another promising approach is the isolation and genetic modification of patients’ cells to target or enhance the efficacy of a cellular therapy. One example of this approach is the development of targeted immunotherapy for B-cell malignancies. To improve immunotherapy for B-cell malignancies, autologous T cells are isolated and genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins made up of antigen-recognition moieties and T-cell activation domains. By targeting the antigen-recognition moiety against antigens that are expressed by B-cell malignancies, such as CD19, CAR-modified T cells eliminate CD19+ leukemia cells with greater efficacy and reduced toxicity. 7 This approach has also been successful in increasing the efficacy of bone marrow–derived mesenchymal stromal cells for the treatment of cardiac infarct. Mesenchymal stromal cells overexpressing protein kinase B show increased cell ARTICLE INFORMATION Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Atala reported that he has received grant support from the National Institutes of Health, the National Cancer Institute, and the Department of Defense, and is a shareholder and board member of Biorg and Plureon. No other conflicts were reported. REFERENCES 1. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676. doi:10.1016/j.cell.2006.07.024.


survivability and functionality within ischemic environment of the infarcted tissue, resulting in improved efficacy of the therapy in regards to reducing inflammation, inhibition of cardiac remodeling, and normalization of systolic and diastolic cardiac function. Similar approaches are currently being investigated to genetically modify cells to enhance cell engraftment, function, and immunomodulatory properties.

The Future Regenerative medicine will continue to progress through multidisciplinary efforts to develop biological tools and therapies. Biological tools such as miniature human organoids are being developed that can accurately model physiological tissue function at the microscale. Often maintained in a microfluidic system, these organs-ona-chip are being developed for the lung, liver, heart, skin, kidney, and others, as well as in a combined system of organoids representing a body-on-a-chip capable of modeling the complex interactions between multiple organ systems. There is a wide range of potential applications for these systems, including disease modeling, drug discovery, and toxicity testing. Future advances in the ability to control and direct cellular activity promises to provide a readily available source of cells for multiple applications. The ability to manipulate cells genetically or with small molecules provides researchers with a valuable tool to design cell therapies to target diseased or injured tissues, for use in tissue-engineered construction or to stimulate regeneration and repair. Biology-based engineering approaches will continue to drive innovation in the field of tissue engineering, with development of cells, materials, and 3-dimensional fabrication strategies specifically for the manufacture of functional tissues. The US Department of Health and Human Services, in its report “2020: A New Vision—A Future for Regenerative Medicine,”8 calls regenerative medicine the “next evolution of medical treatments” and predicts that regenerative medicine will be the “vanguard of 21st century healthcare.” The field is well on its way to fulfilling this prediction.

2. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509-516.

small molecule inhibitors. Proc Natl Acad Sci U S A. 2011;108(20):8299-8304.

3. Shin H, Jo S, Mikos AG. Biomimetic materials for tissue engineering. Biomaterials. 2003;24(24): 4353-4364.

7. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10(5): 267-276.

4. Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol. 2014;32(8):773-785. doi:10.1038/nbt.2958. 5. Li W, Sun W, Zhang Y, et al. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by

6. Qian L, Huang Y, Spencer CI, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400): 593-598..

8. US Department of Health and Human Services. 2020: A New Vision—A Future for Regenerative Medicine. Washington, DC: Dept Health and Human Services; 2006.

JAMA April 14, 2015 Volume 313, Number 14 (Reprinted)

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