OXFORDWINSTON · The effects of lineage differentiation into pancreatic beta-cells on the immunogenicity of amniotic fluid stem cells

Periodic Report Summary - OXFORDWINSTON (The effects of lineage differentiation into pancreatic beta-cells on the immunogenicity of amniotic fluid stem cells)

Dr Orlando has conceived, designed and implemented a ground-breaking project on ex vivo kidney bioengineering. Porcine kidneys are harvested and decellularised with detergents to produce renal extracellular matrix scaffolds. These constructs represent the ideal platform for kidney bioengineering. However, it is important to understand how the immune system reacts following the implantation of such scaffolds. To address this issue, while in Oxford, Dr Orlando has conceived and developed an experimental model for the characterisation of such response. The question to answer was whether inflammasome drives the inflammatory response which follows the implantation of bioengineered ECM, via the IL-1b signalling pathway. The immune system responds to the implantation of bioengineered constructs with a nonspecific inflammatory response orchestrated by the innate compartment. Regardless of the site of implantation, the first relevant event of this process is the contact between biomaterials and whole blood, which follows the haemorrhage caused by the incision. Thereafter, activation of the coagulation, contact and complement systems follows in a domino effect, with the consequent release of myriads of molecules, and the recruitment of cellular elements that altogether will mount the initial acute inflammatory response. As implanted biomaterials are intended to remain in situ indefinitely or until degradation, they tend to generate a foreign body reaction-like response. In fact, in the presence of a persisting stimulus represented by permanent biomaterials, the acute inflammatory response generated by the initial injury to the vascularised connective tissue is destined to perpetuate and evolve, as different cells are recruited over time and the predominant cell type present in the inflammatory milieu varies with the age of the injury. As robust data show that the key molecule in sterile inflammation is interleukin-1b, whose transcription is mediated by the inflammasome system, we developed a murine model to investigate the role of inflammasome in the response to the implantation of acellular murine liver extracellular matrix (alECM). Preliminary RT-PCR results obtained during 12-month research period at the transplant research immunology group at the University of Oxford, show that the implantation of aECM does trigger an inflammatory response in WT, TLR4-/- and RAG-/- mice, comparable to the one observed after the implantation of samples of whole liver.

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