Robinson, Ainsley (2019) Stem cell therapies for the treatment of enteric neuropathy associated with inflammatory bowel disease. PhD thesis, Victoria University.

Abstract

Although not associated with mortality, symptoms, complications and the relapsing nature of inflammatory bowel disease (IBD) severely impact patient’s quality of life. Current treatments are coupled with side effects and loss of patient response. Damage to the enteric neurons is consistently associated with intestinal inflammation and considered to underlie the generation of symptoms. Therefore, the enteric neurons are a potential target for novel IBD therapies. Mesenchymal stem cells (MSCs) exhibit anti-inflammatory, immunomodulating, and neuroprotective effects and are demonstrated to participate in tissue regeneration and repair in many pathological conditions. Hence, they are a viable option for the treatment of enteric neuropathy associated with IBD. The studies in this thesis aim to investigate the effects of MSC therapy in averting enteric neuropathy in acute and chronic models of IBD. The results of our studies demonstrated that MSC and conditioned medium attenuated inflammation and averted enteric neuropathy and colonic dysmotility in an acute model of IBD. The effects of MSC treatment are dose-dependent and occur as early as 24h post treatment. We characterized changes to colonic innervation, motility, transit time, microbiota and metabolome in the Winnie mouse model of spontaneously occurring chronic colitis. Our results demonstrated that the Winnie mouse is highly representative of human IBD. The mechanisms underlying colonic dysmotility in Winnie mice were due to inhibition of neuromuscular transmission and smooth muscle responses. We found that multiple high dose MSC treatments induce anti-inflammatory and neurotrophic effects in mice with chronic colitis. Single dose and multiple low dose MSC administrations were ineffective in this model. Overall, we have established the capacity of MSC treatments to attenuate inflammation and enteric neuropathy in acute and chronic models of IBD. These findings are both novel and highly relevant for clinical translation and future investigations of MSC therapy for the treatment of IBD.

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