Special Issue “Organ Replacement Approaches”

Abstract

Recent progress in the field of tissue engineering has been accelerating since the emergence of ES/iPS technology. This promising collaboration is attracting worldwide attention to developing real-life regenerative therapy using “Organ replacement approaches.” As described by Dr. Gojo, it is still a “black box” even regarding the mechanisms regulating appendage regeneration in the newt, which must be considered a fundamental issue for the development of mammalian adult tissue regeneration. Therefore, at the moment we have to construct regenerative organ structures outside of the body and transplant them in the right way and at the right time. Indications for “organ replacement” therapy have been changing, because surgical procedures and technology for supportive therapies have also been rapidly progressing. Nonetheless, the demand for replacement therapy is still increasing, because more aggressive surgical therapies are now available and more patients can be treated. This is especially the case in oncology, as mentioned by Dr. Hibi in the review of recent progress in organ transplant technology, which may open new avenues for the clinical application of organ replacement approaches in advanced cancer treatment. Dr. Kojima clarified the clinical issues that prevent long-term efficacy of pancreatic β-cell transplantation, emphasizing the importance of (1) three-dimensional reconstitution of islets, (2) appropriate architecture with adhesion molecule expression (cell surface molecules), (3) cell-to-cell contact influenced by the ratio of α- and β-cells (different cell types), and (4) efficient vascularization after transplantation. These issues are exactly the same in every field of organ reconstruction, and to solve each one step by step by solid experimentation is crucial to develop this promising technology for real-life clinical applications. As described, one of the critical issues for creating large-scale regenerative organs rather than micro-scale cultured cell clusters or tissues are clearly to reconstitute efficient three-dimensional tissue structures. Dr. Sudo reviewed different tissue engineering approaches at multiple scales from microelectromechanical systems (MEMS) to cell sheet and organ decellularization. Here, the interface between bottom-up approaches such as MEMS and top-down approaches such as organ decellularization are important. Understanding the role of the extracellular matrix (ECM) in cell behavior is crucial for the seamless structure of three-dimensional tissue with an efficient interface between micro- and macro-construction. Dr. Pedro described the multiple roles of the ECM especially in liver regeneration, suggesting its influence on lineage specification. They also described that cell behavior is greatly influenced by the mechanical environment, including the topography and stiffness of the surrounding tissue, fluid shear stress, and interstitial fluid pressure. Interestingly, stem cell differentiation could be directed toward different lineages by altering the mechanical properties of the substrate to mimic specific tissue types using decellularized scaffolds. Indeed, Dr. Orlando demonstrated the efficacy of PGA scaffolds using adipose- or muscle-derived stem cells. The experiment explored whether the scaffolds seeded with those stem cells promoted greater lymphocyte migration, less fibrosis, and more incorporation into the bladder wall than control, leading to smooth muscle regeneration/migration. The results suggested the importance of cell choice and type of scaffold. Dr. Kadota also reported that MSCs might be good candidates for a supportive cell source for organ regeneration, showing upregulation of adhesion molecules as well as vascular growth factor. Indeed, vascularization is one of the important issues for organ reconstruction as described here. Based on his “Organ bud” technology, Dr. Takebe demonstrated reconstitution of three-dimensional human hepatic tissue from embryonic fetal liver cells mixed with human umbilical vein endothelial cells and hMSCs by implantation into a collagen/fibronectin matrix composite. This study suggested that cell-to-cell contact between mature and immature cell types in structural supports might augment the regenerative capacity of these cells. However, it is still unclear how the co-seeding of progenitor or stem cells affects cell behavior and tissue regeneration. This is discussed in the thoughtful concise review by Dr. Tanimizu and Dr. Mitaka, who focused on the role of liver progenitor cells (LPCs) in the repair of damaged liver tissue with differentiation. Very interestingly, they suggested that LPCs are involved in tissue repair in chronically injured liver, although LPCs supply different lineage cells depending on types of injury. Importantly, they concluded that the balance of LPC activation and mature hepatocyte plasticity might deteriorate in chronic liver injury. In conclusion, to develop clinically-relevant organ replacement approaches, we have to understand not only cell-cell or cell-matrix contacts but also complex behavior of responsive cells including lineage conversion or de-differentiation. However, the use of certain types of tissue scaffold such as decellularized matrix might provide new insights into in vivo tissue alterations, because these are transplantable with efficient vasculature and blood flow, and therefore amenable to long-term observation after implantation. Tracking implanted assembled organs long-term will facilitate understanding the mechanisms of tissue regeneration in situ, which may lead to the clinical application of current “Organ replacement approaches.”