Jevans, BS; (2018) Biology and therapeutic potential of enteric nervous system stem cells for spinal cord injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Spinal cord injury (SCI) is one of the leading and most crippling causes of acquired neurological impairment. It affects around 40,000 individuals in the UK, causing paralysis, multisystem impairment and a reduced life expectancy. This has a devastating impact on quality of life and places stress upon both individuals and healthcare systems. Despite extensive characterization of SCI pathology, there remains no cure. Stem cells offer a potential therapy since they can replace lost neurons, promote axonal regeneration and limit scar formation, but an optimal stem cell source has yet to be found. Enteric neural stem cells (ENSCs) are a possible solution. ENSCs comprise the renewing population of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal (GI) tract. ENSCs can be isolated from the GI tract via minimally invasive techniques such as endoscopy, and when transplanted into aneural or dysfunctional gut, are capable of reforming a functional ENS. This thesis assesses the potential of ENSCs as a stem cell source for SCI. Chimeric neural tube grafting was used to fluorescently label chick ENSCs, allowing for isolation and lineage tracing. In vitro characterization revealed neuronal subtypes that were common between ENSCs and spinal cord tissue. Following transplantation into the embryonic chick spinal cord ENSCs survived, differentiated into neurons and formed anatomical bridges across the injury zone. In an adult rat model of SCI, ENSC transplantation was combined with application of chondroitinase ABC (ChABC), a modifier of the inhibitory microenvironment observed within SCI. ENSCs, when transplanted on their own, demonstrated extended survival, differentiated into neurons and bridged the injury site. Combined treatment (ENSCs + ChABC) resulted in a significant improvement in lesion histology, including reduction of the injury cavity, and increased numbers of endogenous axons crossing the injury site. Together, these findings establish ENSCs as a promising alternative stem cell source for SCI.

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