Regenerative medicine as applied to solid organ transplantation: current status and future challenges

Abstract

Summary In the last two decades, regenerative medicine has shown the potential for “bench-to-bedside” translational research in specific clinical settings. Progress made in cell and stem cell biology, material sciences and tissue engineering enabled researchers to develop cutting-edge technology which has lead to the creation of nonmodular tissue constructs such as skin, bladders, vessels and upper airways. In all cases, autologous cells were seeded on either artificial or natural supporting scaffolds. However, such constructs were implanted without the reconstruction of the vascular supply, and the nutrients and oxygen were supplied by diffusion from adjacent tissues. Engineering of modular organs (namely, organs organized in functioning units referred to as modules and requiring the reconstruction of the vascular supply) is more complex and challenging. Models of functioning hearts and livers have been engineered using “natural tissue” scaffolds and efforts are underway to produce kidneys, pancreata and small intestine. Creation of custom-made bioengineered organs, where the cellular component is exquisitely autologous and have an internal vascular network, will theoretically overcome the two major hurdles in transplantation, namely the shortage of organs and the toxicity deriving from lifelong immuno-suppression. This review describes recent advances in the engineering of several key tissues and organs.

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

“…Creation of custom-made bioengineered organs, where the cellular component is exquisitely autologous and have an internal vascular network will theoretically overcome the two major hurdles in transplantation, namely the shortage of organs and the toxicity deriving from lifelong immunosuppression. Advances in transplantation of custom-made organs have been described (Orlando et al, 2011b). The uses of hESC and hMSC in regenerative therapies will be described in section 6.1.…”

Operational Tolerance after Renal Transplantation in the Regenerative Medicine Era

“…In the last decade, investigators in the field have been able to produce and implant in patients relatively simple hollow organs like skin [Naughton et al, 1999], vessels [Hibino et al, 2010;L'Heureux N et al, 2007;McAllister et al, 2009;Shinoka et al, 2001;Shinoka et al, 2005;], bladders [Atala et al, 2006], windpipes [Macchiarini et al, 2008] and urethras [RayaRivera et al, 2011]. Importantly, all constructs were manufactured by either combining autologous cells with scaffolding material, or through the engineering of autologous cells per se [Orlando, Baptista et al, 2010;Orlando et al, 2011]. Importantly, none of the patients did require IS at any time after implantation of the bioengineered body part.…”

“…The term regenerative medicine refers to that field in the health sciences which aims to replace or regenerate human cells, tissues, or organs in order to restore or establish normal function [Mason & Dunnill, 2008;Orlando, Baptista et al, 2010;Orlando et al, 2011]. The process of regenerating body parts can occur in vivo or ex vivo and may require cells, natural or artificial scaffolding materials, growth factors, or different combinations of all three elements.…”

“…Moreover, in several circumstances, patients who could be weaned off IS eventually rejected and required resumption of IS. Bioengineering technology has been implemented to manufacture heart [Ott et al, 2008], liver [Badylak et al, 2011;Baptista et al, 2011;Uydun et al, 2010;] and lung [Ott et al, 2010;Petersen et al, 2010;] organoids from rodent organs [Orlando, Baptista et al, 2010;Orlando et al, 2011]. In extenso, rat or ferret organs were decellularized with detergents and repopulated with cells from unrelated species, humans included.…”

Sisyphus, the Giffen's paradox and the Holy Grail: time for organ transplantation to transition toward a regenerative medicine-focused type of research

“…In the past 20 years, over 160 patients have received organs manufactured from autologous cells, which -in most cases -were seeded and expanded on a supportive scaffold and eventually transplanted into a patient, without any need for immunosuppression (IS) at any time after the implantation [2][3][4][5][6][7]. With these significant achievements, organ bioengineering and regeneration (OBR), a field of health sciences falling under the umbrella of regenerative medicine (RM), has shown the potential to revolutionize organ transplantation by addressing the two most urgent concerns: the need for an inexhaustible source of organs and the accomplishment of an IS-free state (IFS; more commonly referred to as tolerance).…”