“The natural healing force within each one of us is the greatest force in getting well” Hippocrates.
There seems to be no better definition of regenerative medicine than the one provided by the father of the medical science about 400 BC. Hippocrates recognized the value of regenerative medicine as an internal potential stemming from the body itself and its ability to heal diseases. The term “regenerative medicine,” however, appears at the medical literature as late as the 1990s and indicates the replacement of cell tissues or organs through inert processes.1 On the other hand, any kind of transplantation implies the anatomical and functional replacement of a cell, a tissue or an organ based on a transfer of an external tissue to the diseased organism. The origin of the replacement tissue is the major difference between regenerative medicine (replacement of internal origin) and transplantation (replacement of external origin).2 Although diametrically opposed at first sight, regenerative medicine and transplantation share much more common grounds than the replacement of diseased tissue.
At the current issue of the journal, Orlando et al provided an excellent overview of regenerative medicine approached through the prism of cell, tissue, and organ transplantation.3 The authors mentioned the differences between the 2 approaches of tissue replacement, further on, they recognized the profound potential of regenerative medicine not only to complement but also to revolutionize transplantation medicine. The potential or regenerative tissue to enable the production of transplant grafts “on demand” can not only expand the donor pool but also boost the quality of the transplanted tissue and subsequently improve outcomes. The perspective of regeneration medicine in the context of transplantation research has rarely been touched in the past. The main merit of the article is the establishment of this connection on the basis of a new definition of regenerative medicine which not only takes into account the needs of transplantation medicine but also addresses solutions to several shortcomings: the use of tissue engineered organs to account for the paucity of transplant organs is an extremely important argument to allow the concept of organs on demand. This concept implies the engineering of tissues from other species (tissue engineered xenotransplantation) from the same species (tissue engineered allotransplantation) or even from the recipient himself/herself.4 Although each of these steps have been described in feasibility studies in the literature, the standardized implementation of the concept to human recipients will take several years. Although the decellularization and reseeding process has been well established in different organs, the survival of the reseeded cells and the integration of the organ to the host still remain unsolved.5
The use of recipient-autologous cells for seeding engineered grafts may be the solution to the issue of graft rejection and the need for immunosuppression. The technique of decellularization will play an enormous role in terms of tolerance induction against cellular immune reaction. The potential role of this process has been identified at an early stage and has been refined during the last years.6 The remaining tissue expresses low or no immunogenic epitopes, and the efficacy of this principle has been demonstrated in several studies. On the other hand, the battle of the remaining tissue in the form of extracellular matrix is still open.7 The latter has been shown to possess both immune-activating as well as immune-modulating properties which may either increase or decrease cellular reaction. An interesting alternative emphasizes the use of bioscaffolds as recipient's cell carriers which per nature are immunologically neutral.
An answer to many questions would be the improvement of stem cell technology in terms of chemoattraction to the area of interest, proliferation and differentiation. The need for blood and oxygen supply is still the limiting factor for endogenous tissue repair. Even if chemoattraction works to a great extent at the time of organ damage, the lack of physiological oxygen and nutrient conditions has a negative impact on proliferation and differentiation. The latter has always been considered as the major drawback of regenerative medicine, as it does not seem to take place at least at a detectable extent.8 Cell reprogramming and induction of pluripotency have been proposed as alternatives and may have an impact in transplantation research too. This may imply the use of reprogrammed cells or pluripotency induction in both bioscaffolds or decellularized donor tissues. Different regeneration capabilities have been attested to the different stem cells types, such as the low in vitro expansion of adult and the effectively nonexisting differentiation potential of adult stem cells as opposed to embryonic stem cells. The latter are mainly affected by ethical considerations as well as the risk of xenocontamination in cases of coculture. Last but not the least, both embryonic stem cells as well as induced pluripotent cells are prone to tumorgenicity, which remains one of the major drawbacks of cells with high regeneration capabilities.9
Although the article provides an overview of the common ground of regenerative medicine and transplantation, it still lacks some information on the optimal stage of differentiation and maturation of stem cells used. The functionality of the replacing tissue is not addressed at the report and should be emphasized once more. At which extent can a transplanted tissue-engineered organ be integrated into the environment of the surrounding tissue and more importantly to which extent can the replacing cells or tissue become an integral part of the healthy residual organ?10 These are questions which may get different answers according to the tissue of interest, they are still of utmost importance for organs with high functional affinity between the cells, such as the heart and the kidney.
This brings up the topic of personalized medicine, which seems to dominate discussions on therapeutic strategies in the future. The use of 3D-printed structures and organs according to the individual needs of each patient is a good example of the marriage between technique and technology. The major part of this technique reflects developments in the printing of scaffolds which can be then enriched with the cells needed to provide some kind of organ or tissue replacement. The field of bioprinting is gaining importance as the extracellular matrix of the donor tissue can be used as a theoretical “bioscaffold” which plays the role of the diseased organ but lacks the existence of accompanying tissue and vasculature.
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2. Orlando G, Wood KJ, Stratta RJ, et al. Regenerative medicine and organ transplantation: past, present, and future. Transplantation
3. Orlando G, Murphy SV, Clancy MJ, et al. Rethinking regenerative medicine from a transplant perspective (and vice versa). Transplantation
4. Willyard C. Timeline: Regrowing the body. Nature
5. Song JJ, Guyette JP, Gilpin SE, et al. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med
6. Guyette JP, Charest JM, Mills RW, et al. Bioengineering human myocardium on native extracellular matrix. Circ Res
7. Fishman JM, Lowdell MW, Urbani L, et al. Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model. Proc Natl Acad Sci U S A
8. Porrello ER, Mahmoud AI, Simpson E, et al. Transient regenerative potential of the neonatal mouse heart. Science
9. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer
10. Higuchi T, Miyagawa S, Pearson JT, et al. Functional and electrical integration of induced pluripotent stem cell-derived cardiomyocytes in a myocardial infarction rat heart. Cell Transplant