Engineered neural tissue with columns of aligned Schwann cell-like cells from differentiated adipose-derived stem cells can support and guide neuronal growth in vitro

Georgiou, Melanie; Kingham, Paul; Golding, Jon; Loughlin, Jane and Phillips, James (2012). Engineered neural tissue with columns of aligned Schwann cell-like cells from differentiated adipose-derived stem cells can support and guide neuronal growth in vitro. In: 3rd International Conference on Stem Cell Engineering "Designing Cellular Therapies", 29 Apr - 02 May 2012, Seattle, US.



There is a clear unmet need in the repair of nerves where damage has resulted in a long gap (more than 4cm in length) – the current clinical ‘gold standard’ is to use an autograft which causes donor site morbidity, has limited availability and often leads to poor functional outcome. Current clinically approved alternatives are hollow nerve guidance conduits (NGCs), which lack the trophic support and guidance cues provided by Schwann cells in an autograft, thus limiting their use to treating a relatively short lesion only. A desirable characteristic for a peripheral nerve repair scaffold is the ability to direct neuronal growth across a lesion to shorten the delay of reinnervation and improve functional recovery after injury. The addition of intraluminal guidance structures to hollow NGCs alone is not sufficient to increase functional recovery; the creation of a more conductive microenvironment is essential. Tissue-engineered cellular bridging devices for surgical implantation into peripheral nerve injury sites could provide an attractive alternative to the autograft. Schwann cells are the highly preferred cell type in such a repair because of their ability to enhance axon migration and secrete factors that further increase regeneration. Using autologous cells in such a therapy would remove many of the challenges associated with allogeneic cellular treatments. However the use of autologous Schwann cells has a number of disadvantages, including the sacrifice of host nerve tissue for their extraction and slow expansion times in vitro. An alternative is to use a patient’s own adipose tissue as a source for adipose derived stem cells (ADSC) that can be differentiated towards a Schwann cell-like phenotype in vitro (dADSC). dADSCs provide the trophic support and pro-regenerative behaviour elicited by Schwann cells in an autograft. They can be incorporated within a 3-dimensional collagen environment that permits cellular self-alignment, to provide a trophic and topographical tissue cable to form the basis of an intraluminal guidance substrate in a peripheral nerve repair device. Here we report the development of a living replacement tissue which mimics key cellular and extracellular features of the autograft endoneurium, using therapeutically relevant cells in an engineered neural tissue (ENT). ENT is made from a cellular collagen gel that is tethered at each end to permit the cells to self-align and form columns of aligned dADSCs; this is subjected to a compression process to produce a stable robust biomaterial with the correct tissue architecture. Experiments using cell death assays, immunostaining and confocal microscopy show that dADSCs can be successfully incorporated within ENT and maintain their phenotype - dADSCs in collagen gels survive and maintain their alignment following the stabilisation process to form sheets of an aligned cellular collagen biomaterial (ENT). Dissociated dorsal root ganglion neurons growing on the surface of ENT extended neurites that were guided by the orientation of the aligned dADSCs. These sheets of ENT containing autologous cells that support and guide neuronal growth, are being integrated into a repair device by rolling ENT into columns, which are then packed together within a clinically approved tube, NeuraWrapTM. Testing this ‘engineered endoneurium’ within a clinically approved conduit in vivo will demonstrate the potential of the device to offer a realistic alternative to nerve autografts.

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