Mesenchymal stem cell treatment for enteric neuropathy in the Winnie mouse model of spontaneous chronic colitis

Abstract

Inflammatory bowel disease (IBD) is a chronic gut inflammation with periods of acute flares and remission. Beneficial effects of a single dose of mesenchymal stem cell (MSC)-based treatment have been demonstrated in acute models of colitis. No studies investigated therapeutic effects of MSCs for the attenuation of enteric neuropathy in a chronic model of colitis. The short and long-term effects of MSC treatment in modulating inflammation and damage to the enteric nervous system (ENS) were studied in the Winnie mouse model of spontaneous chronic colitis highly representative of human IBD. Winnie mice received a single dose of either 1 × 10⁶ human bone marrow-derived MSCs or 100µL PBS by intracolonic enema. C57BL/6 mice received 100µL PBS. Colon tissues were collected at 3 and 60 days post MSC administration to evaluate the short-term and long-term effects of MSCs on inflammation and enteric neuropathy by histological and immunohistochemical analyses. In a separate set of experiments, multiple treatments with 4 × 10⁶ and 2 × 10⁶ MSCs were performed and tissue collected at 3 days post treatment. Chronic intestinal inflammation in Winnie mice was associated with persistent diarrhea, perianal bleeding, morphological changes, and immune cell infiltration in the colon. Significant changes to the ENS, including impairment of cholinergic, noradrenergic and sensory innervation, and myenteric neuronal loss were prominent in Winnie mice. Treatment with a single dose of bone marrow-derived MSCs was ineffective in attenuating chronic inflammation and enteric neuropathy in Winnie.

Keywords: Enteric nervous system; Enteric neuropathy; Inflammatory bowel disease; Intestinal inflammation; Mesenchymal stem cells; Spontaneous chronic colitis.