In my younger years, I was a big fan of Thunderbirds, a TV series about the Tracy family, whose head was Jeff Tracy, an American ex-astronaut. Their organization possessed technologically advanced land, sea, air, and space vehicles, which were called into service when conventional rescue techniques proved ineffective in saving human life.1 The authors of this series were inspired by a real-life rescue attempt in an iron mine in Germany in which the authorities were forced to use a risky, highly unconventional approach to save the mineworkers' lives. To me, this is a metaphor for how growing organs on chip, repairing organs on the pump, three-dimensional printing of organs, recellularization of organ scaffolds, organ patches, synthetic tissues, and the use of artificial cells has developed. If you had asked me 10 to 15 years ago, I would never have believed that these things could become true. For example, the functionality of bioengineered lungs is being tested in a porcine transplant model and immune tissue in small animal models.2,3 These 2 examples show that huge strides have been made in tissue engineering, and that transplanting of this kind of organ might become possible. In addition, research on organ repair and regeneration is making progress. It is clear that things in this field are moving on apace!
This issue of Transplantation highlights the latest developments in the field of tissue engineering, repair, and regeneration for organ transplantation. We report how innovative technologies, improved reagents for cell expansion and tissue engineering, availability of improved methods for organ preservation, and acquired knowledge on processes involved in both the acute response and the regenerative phase of tissue repair are rapidly pushing developments in this field forward. The major breakthrough came in 2006 when Takahashi and Yamanaka published their cutting-edge article on programming mature cells to induced pluripotent cells (iPSC).4 These cells have been shown to be capable of development toward kidney, heart, lung, liver, and other structures, also named organoids or mini organs.2,4-6 In this issue, the overview article by Orlando et al7 addresses state-of-the-art iPSC-derived organoids. Human iPSC-derived organoids provide a new animal-free tool to study complex mechanisms at an early stage of the processes involved in tissue injury and which feed the cascades leading to organ failure in patients after transplantation. For example, a small functional kidney unit offers a unique opportunity to understand the biology of human kidney inflammation and the contribution of the immune system in this process in a “clean” environment.7,8 In this test system, there are no other bystander factors influencing the interaction of elements of the immune system with the organ or affecting its function. By using such an approach molecules and cells activated by the complement system, macrophages and other immune cells mediating kidney damage can be identified. These organoids can also be used to study the efficacy of agents for the treatment of kidney injury to identify biomarkers for the early detection of tissue injury and the effects of immunosuppressive drugs on tissue cells. However, these findings come with a warning. Reports showing clinical applications often create unrealistic expectations. Organoids are primitive, fetal tissues, and are not vascularized.7,8 This limits their functionality and possibilities for transplantation and better protocols and models are needed to provide vascularization and thus improve the function of organoids in vivo.
Fundamental research unraveling the processes in tissue injury, repair, and regeneration demonstrated a crucial role for stromal stem cells. Key features of these cells are the secretion of trophic factors, immunomodulatory and (de)differentiation capacities.9 Research is ongoing on the therapeutic effect of mesenchymal stem cells (MSC) to minimize donation-related injury by reducing inflammation and immunogenicity and to improve immediate graft function in high-risk donor kidney and liver transplantation. The study by Brasile et al10 demonstrates that ischemically damaged human kidneys from donors after circulatory death and warm perfused for 24 hours ex vivo with MSC do well. Compared with a perfused control kidney not receiving MSC, there was increased synthesis of adenosine triphosphate, reduced inflammatory response, increased synthesis of growth factors, and normalization of the cytoskeleton and mitosis. These promising data show that tissue regeneration is possible. For understandable reasons, the authors used discarded kidneys and the number of studied, perfused kidneys was small. Despite these limitations, this is the first report showing the potential of MSC to repair damaged donor kidneys ex vivo.
There is also much progress in the area of organ perfusion research. Questions currently on the table are: (1) hypothermic machine perfusion or normothermic machine perfusion (NMP) and (2) the need for oxygen support, both of which are discussed in several papers published in this issue.11-16 One of these is the study by Kabagambe and colleagues,14 who report on kidneys that were deemed unsuitable for transplantation. The authors show that these organs can improve in quality and function when receiving oxygen and NMP. Five of 7 human kidneys with long cold ischemia times and/or poor hypothermic parameters placed on ex vivo normothermic perfusion using oxygenated red blood cells, and supplemental nutrition showed clear signs of recovery.14 These kidneys produced urine with increasing creatinine clearance. If and how these organs would function was not a question addressed in this study but is a fundamental next step. This will have to prove that discarded organs can be used for transplantation if well preserved and perfused. Significant advances have also been made in preserving organ quality in liver donation. The cutting-edge article by the Oxford group on NMP and liver graft injury demonstrated the efficacy of this technology over conventional cold storage.17 In their randomized-controlled trial the authors demonstrated that NMP is associated with a 50% lower level of liver graft injury. It is good to realize that apart from these beneficial effects on graft function also costs are a factor to be taken into account. For example, prolonged cold ischemia time and the subsequent delayed graft function significantly increase the transplantation related costs.18 In addition, data from the Australian and New Zealand Dialysis and Transplant registry showed that duration of delayed graft function is associated with an increased risk of acute rejection and death-censored graft loss.19
The last topic of this commentary is the search for biomarkers for tissue injury.20-22 Currently, the evaluation of organ quality relies on the assessment of surrogate organ function markers, donor age, and histology during donor management. As described by Kaisar et al22 these are subjective measures that are far from optimal and do not predict allograft performance. In a pilot study, the authors used mass spectometry to determine donor tissue proteomic profiles. These protein profiles differentiated between kidneys that perform well and those that have suboptimal function on the basis of the 3-month posttransplantation outcomes of the pairs of kidney recipients from the same donor. Again, this is a step forward in the search for better quality organs for transplantation.
The research described in this commentary is motivated by the increasing demand for organ transplantation, the shortage of available organs, and the prevention of primary nonfunctioning grafts.7-10,14,17,19,23 Therefore, acceptance of expanded criteria donor organs with the consequence of a higher risk of unfavorable transplantation outcomes has become an increasing reality. Prevention of tissue injury, a better measure to determine the degree of organ injury, repair of damaged organs, or even tissues grown in the laboratory, will all mean that more organs can be used for transplantation. To achieve these ambitions, we the transplant professionals, have to show courage, work out of the box, and sometimes just do it. To repeat the words of Mark Victor Hansen “Don't wait until everything is just right. It will never be perfect. There will always be challenges, obstacles and less than perfect conditions. So what. Get started now. With each step you take, you will grow stronger and stronger, more and more skilled, more and more self-confident and more and more successful.”24 Only with such an attitude will we achieve our common goal: reducing donor organ shortage. Regenerative medicine is crucial for this and—to paraphrase Thunderbirds—“Repairing tissues are go!” (Figure 1). Enjoy reading this month's issue of Transplantation on tissue injury, repair, and regeneration.
1. Thunderbirds [TV Series]. AllMovie
. San Francisco, CA: All Media Network; 1965:2015.
2. Gosselin EA, Eppler HB, Bromberg JS, et al. Designing natural and synthetic immune tissues. Nat Mater
3. Nichols JE, La Francesca S, Niles JA, et al. Production and transplantation of bioengineered lung into a large-animal model. Sci Transl Med
4. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell
5. Takasato M, Er PX, Chiu HS, et al. Generation of kidney organoids from human pluripotent stem cells. Nat Protoc
6. Ishida M, Miyagawa S, Saito A, et al. Transplantation of human induced pluripotent stem cell-derived cardiomyocytes is superior to somatic stem cell therapy for restoring cardiac function and oxygen consumption in a porcine model of myocardial infarction. Transplantation
7. Orlando G, Murphy S, Bussolati B, et al. Rethinking regenerative medicine from a transplant perspective (and vice versa). Transplantation
8. Shankar A, Hoorn EJ, Gribnau J, et al. Current state of renal regenerative therapies. Transplantation
9. Reinders MEJ, van Kooten C, Rabelink TJ, et al. Mesenchymal stromal cell therapy for solid organ transplantation. Transplantation
10. Brasile L, Henry N, Orlando G, et al. Potentiating renal regeneration using mesenchymal stem cells. Transplantation
11. Sedigh A, Nording S, Carlsson F, et al. Perfusion of porcine kidneys with macromolecular heparin reduces early ischemia reperfusion injury. Transplantation
12. Martins PN, Berendsen TA, Yeh H, et al. Oxygenated UW solution decreases ATP decay and improves survival after transplantation of DCD liver grafts. Transplantation
13. Yu Y, Cheng Y, Pan Q, et al. Effect of the selective NLRP3 inflammasome inhibitor mcc950 on transplantation outcome in a pig liver transplantation model with organs from donors after cardiac death preserved by hypothermic machine perfusion. Transplantation
14. Kabagambe S, Palma IP, Smolin Y, et al. Combined ex-vivo hypothermic and normothermic perfusion for assessment of high-risk deceased donor human kidneys for transplantation. Transplantation
15. Komatsu H, Rawson J, Medrano L, et al. Optimizing temperature and oxygen supports long-term culture of human islets. Transplantation
16. Patel K, Smith T, Neil D, et al. The effects of oxygenation on ex vivo kidneys undergoing hypothermic machine perfusion. Transplantation
17. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature
18. Serrano OK, Vock DM, Chinnakotla S, et al. The relationships between cold ischemia time, kidney transplant length of stay, and transplant-related costs. Transplantation
19. Lim WH, Johnson DW, Teixeira-Pinto A, et al. Association between duration of delayed graft function, acute rejection and allograft outcome after deceased donor kidney transplantation. Transplantation
20. Pagano D, Badami E, Conaldi PG, et al. Liver perfusate natural killer cells from deceased brain donors and association with acute cellular rejection after liver transplantation: a time-to-rejection analysis. Transplantation
21. Roest HP, Ooms LSS, Gillis AJM, et al. Cell-free microRNA miR-505-3p in graft preservation fluid is an independent predictor of delayed graft function after kidney transplantation. Transplantation
22. Kaisar M, Dulleman van L, Akhtar ZM, et al. Subclinical changes in deceased donor kidney proteomes are associated with 12-month allograft function post transplantation—a preliminary study. Transplantation
23. Singh Avtaar Singh A, Banner NR, Rushton S, et al. ISHLT primary graft dysfunction incidence, risk factors and outcome: a UK National Study. Transplantation