Abstract
BackgroundThe use of mesenchymal stem cells (MSCs) to treat inflammatory bowel disease (IBD) is of great interest because of their immunomodulatory properties. Damage to the enteric nervous system (ENS) is implicated in IBD pathophysiology and disease progression. The most commonly used model to study inflammation-induced changes to the ENS is 2,4,6-trinitrobenzene-sulfonate acid (TNBS)-induced colitis in guinea pigs; however, no studies using guinea pig MSCs in colitis have been performed. This study aims to isolate and characterise guinea pig MSCs and then test their therapeutic potential for the treatment of enteric neuropathy associated with intestinal inflammation.MethodsMSCs from guinea pig bone marrow and adipose tissue were isolated and characterised in vitro. In in vivo experiments, guinea pigs received either TNBS for the induction of colitis or sham treatment by enema. MSCs were administered at a dose of 1 × 106 cells via enema 3 h after the induction of colitis. Colon tissues were collected 24 and 72 h after TNBS administration to assess the level of inflammation and damage to the ENS. The secretion of transforming growth factor-β1 (TGF-β1) was analysed in MSC conditioned medium by flow cytometry.ResultsCells isolated from both sources were adherent to plastic, multipotent and expressed some human MSC surface markers. In vitro characterisation revealed distinct differences in growth kinetics, clonogenicity and cell morphology between MSC types. In an in vivo model of TNBS-induced colitis, guinea pig bone marrow MSCs were comparatively more efficacious than adipose tissue MSCs in attenuating weight loss, colonic tissue damage and leukocyte infiltration into the mucosa and myenteric plexus. MSCs from both sources were equally neuroprotective in the amelioration of enteric neuronal loss and changes to the neurochemical coding of neuronal subpopulations. MSCs from both sources secreted TGF-β1 which exerted neuroprotective effects in vitro.ConclusionsThis study is the first evaluating the functional capacity of guinea pig bone marrow and adipose tissue-derived MSCs and providing evidence of their neuroprotective value in an animal model of colitis. In vitro characteristics of MSCs cannot be extrapolated to their therapeutic efficacy. TGF-β1 released by both types of MSCs might have contributed to the attenuation of enteric neuropathy associated with colitis.
Highlights
The use of mesenchymal stem cells (MSCs) to treat inflammatory bowel disease (IBD) is of great interest because of their immunomodulatory properties
We present data on the isolation, in vitro characterisation and in vivo application of allogeneic MSCs for the treatment of enteric neuropathy associated with experimental colitis in guinea pigs
In vitro validation of gpBM-MSCs and gpAT-MSCs and characterisation of their morphology and growth kinetics To examine the immunophenotype of guinea pig MSCs, cells were analysed by flow cytometry for the presence of positive MSC markers CD29, CD44, CD73 and CD90 and negative MSC markers CD34 and CD45
Summary
The use of mesenchymal stem cells (MSCs) to treat inflammatory bowel disease (IBD) is of great interest because of their immunomodulatory properties. Damage to the enteric nervous system (ENS) is implicated in IBD pathophysiology and disease progression. Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn’s disease, is a chronic debilitating disorder currently increasing in incidence and prevalence [1]. Current treatment options include anti-inflammatory drugs (aminosalicylates), corticosteroids, immunomodulators (thiopurines, methotrexate and cyclosporine) and biological agents (anti-tumour necrosis factor-alpha); these treatments either are toxic in the long term or frequently fail to induce and maintain remission [3]. Patients unresponsive to therapy require removal of inflamed bowel segments; incidentally, almost 30 % of patients with Crohn’s disease will undergo their first bowel resection surgery within 7 years of diagnosis and subsequently require repeated surgeries [4]. Using live cells to modify the inflammatory response, as opposed to conventional drugs, remains an intriguing prospect
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