Regenerative Medicine: The Next Frontier

Organ transplantation has revolutionized modern medicine, extending the lives of countless patients with failing hearts, lungs, kidneys, pancreas, and intestines. This achievement is attributable not only to crucial advances in surgical technique and critical care medicine, but also to gains made at the bench top. In large part, research advances that have furthered our understanding of the complexities of the immune system and facilitated the development of effective immunosuppression are responsible for the current success of organ transplantation. Similarly, current basic science efforts in regenerative medicine, such as that presented by Dr. Atala and coworkers in this issue of Transplantation, stand poised to provide alternative therapies for current gaps in the treatment of diseased or absent tissue. Most immediate are those patients waiting for solid organ transplantation, who may not receive one, because of the shortage of donor organs. Furthermore, given the requirement for life-long immunosuppression and its accompanying risks, allogeneic transplantation has not been extended as a standard therapeutic option for the treatment of diseased or absent tissue which do not pose life-threatening risks, such as urogenital or soft tissue defects. In these instances, surgeons have devised a host of complex reconstructive approaches, modifying autologous tissue or organs to serve as substitutes or employing anyone of the several synthetic or processed allogeneic materials. As a whole, however, these approaches violate the well-established reconstructive surgery paradigm of replacing “like with like,” often resulting in suboptimal functional outcomes, at a minimum, and complications, in worse case scenarios. The pioneering work by Dr. Atala and coworkers on bioengineering of urogenital tissue highlights the progress of regenerative medicine. The ultimate aim of this approach is to regenerate the missing or diseased tissue by bringing together the proper combination of cells, scaffold material, and environmental cues. Atala et al. (1) has previously demonstrated the clinical utility of such an approach for engineering urinary bladders. Now Dr. Atala and coworkers have remarkably applied this approach to create a functional neo-vagina. Dr. Atala and coworkers seeded smooth muscle and epithelial cells on a polyglycolic acid scaffold, cultured the construct in a bioreactor for 7 days, and implanted the construct in place of the native vagina in an autologous fashion in rabbits. This study is undoubtedly exciting for the prospects that it brings for women who lack their genital track, but it also sheds light on key issues that confront researchers in regenerative medicine. In the design of cell-based therapies, one of the first decision points is determining what source of cells to employ. In this article, Dr. Atala and coworkers used autologously harvested smooth muscle and epithelial cells. The unique niche environment created by the implanted scaffolds seeded with cells is demonstrated by the patent neo-vaginas at the 6-month time point, in contrast to rabbits implanted with constructs alone, which exhibited strictured or collapsed vaginas at early time points and uniform absence of a vagina at the 6-month time point. Dr. Atala and coworkers also demonstrated the advantage of using lineage committed cells. Their implantation of smooth muscle and epithelial cells ensures that the resulting neo-vagina would not have undesired tissue types. However, use of lineage committed cells often requires harvest of the very tissue which is in need of reconstruction. In many instances, this tissue is absent, limited, or not suitable for harvest because of scar formation from previous surgery or radiation exposure. Investigations into other potential cellular sources for tissue engineering applications are at an exciting crossroad. Considerable attention has been directed at characterizing many sources of multipotent cells that can be easily harvested and employed for cell-based tissue engineering including bone marrow, adipose, amniotic fluid, umbilical cord blood, dental pulp, and skeletal muscle, among others (2–8). Although embryonic stem cells (ESCs) are at the apex of the multipotency hierarchy, concerns about the tumorigenic potential of ESCs, in addition to ongoing ethical and political debates on human ESCs, precludes their immediate application to regenerative medicine (9, 10). More recently, the demonstration by two independent groups, Yamanaka and Thomson, of induced pluripotency in adult, somatic cells adds another dimension to potential cell sources for regenerative medicine (11, 12). Although these studies remain proof of principle experiments, they introduce the possibility for reprogramming adult human somatic cells, such as skin fibroblasts, into a specific lineage with the appropriate cocktail of genes. Given the multitude of cellular sources currently available, it is unclear what the most appropriate cellular source may be. Although this may indeed vary depending on the tissue or organ of interest, it remains critically important to fully understand the biological mechanisms controlling differentiation along a specific lineage of all cell types, including ESCs and induced pluripotent cells. In a cell-based approach, it would be ideal to have the ability to autologously harvest cells and employ them with minimal to no ex vivo manipulation. Ultimately, the goal is to identify cells that can be easily harvested, differentiated consistently along the lineage of interest, and most importantly, pose minimal risk to the patient. It is also noteworthy that Dr. Atala and coworkers found good vascularity of the implanted neo-vaginas at the later time points. Undoubtedly, the foresight of the authors to wrap the implanted construct with omentum contributed to the successful vascularization of the neo-vagina. This element of their experimental design highlights the need for a vascular supply as the size of the bioengineered constructs increase. It is foreseeable in instances where the recipient’s vascular supply, such as the omentum, has previously been resected, the bioengineered construct would have to provide its own stimuli for blood vessel formation. Efforts aimed at providing a vascular supply for bioengineered constructs are proceeding along a two-pronged approach. Numerous groups are investigating the most efficient scaffold formulations for delivering proangiogenic factors, such as vascular endothelial growth factor, to stimulate de novo blood vessel formation (13, 14). Simultaneously, a concerted effort is also being directed at engineering blood vessels themselves through the proper combination of cells and scaffold material (15, 16). Finally, Dr. Atala and coworkers are to be commended for their demonstration of the functional qualities of the neo-vagina. The authors demonstrated tensile strength of the construct comparable with native vaginal tissue, and the ability of the engineered tissue to contract in response to electrical and pharmacological stimuli. As progress in vaginal regeneration proceeds, it is certain that future work will also forge into engineering of associated glands that would provide lubrication to the neo-vagina. The rigor that Dr. Atala and coworkers took towards validating the function of the neo-vagina emphasizes the importance of demonstrating functional competence of the engineered tissues or organs. The need for improved treatment modalities for patients with diseased or absent tissue is clear. Concurrent progress in the multidisciplinary field of regenerative medicine provides hope that it may one day provide solutions to current shortcomings in our treatment of missing or diseased tissue and organs. Just as the success of solid organ transplantation was based on basic science research, the ability to fully translate regenerative medicine into the clinical arena will likewise depend on rigorous research in this arena.