Abstract
Mesenchymal stromal cells (MSC) are widely studied for their immunosuppressive and anti-inflammatory activities in the treatment of a number of immune-related disorders, in particular,Graft versus Host Disease (GvHD) and Inflammatory Bowel Disease (IBD). Clinical studies have confirmed MSC safety and efficacy in patients, although the underlying mechanisms remain poorly elucidated.Recent work from our group has demonstrated that MSC-mediated immunomodulation results from the induction of apoptosis by cytotoxic cells.In this project, we have investigated the physiological and clinical impact of apoptotic MSC (ApoMSC) in inflammation. In particular, we have addressed the following hypothesis:
1. Whether the ability of stromal cells to undergo PBMC-induced apoptosis is selective and regulated by the inflammatory microenvironment.
2. Whether PBMC-induced MSC apoptosis can be detected in different inflammatory disorders and resolve the underlying mechanisms
3. Whether the ability of patients’ PBMC to induce apoptotic signalling pathways in MSC can be regarded as a predictive biomarker of clinical response to MSC infusions.
We have found that stromal cells are selectively susceptible to undergo apoptosis when in contact with activated cytotoxic cells. The susceptibility is influenced by pro-inflammatory soluble factors but not by hypoxic conditions. Mechanistically, MSC killing is mediated by direct contact with NK cells and is at least partially dependent on the engagement of NKG2D and DNAM-1 receptors and on the release of granzymes. Apoptotic MSC upregulate the expression of the enzyme cyclooxygenase 2 (COX-2) and the production of its metabolite prostaglandin E2 (PGE2) in a caspase-dependent manner. The induction of ApoMSC inhibits peripheral blood mononuclear cells (PBMC) activation and the effect is abolished after inhibition of COX2 activity.
We have also tested the role of these mechanisms in predicting clinical responses in IBD patients. The analysis of a phase3 randomised, double-blind controlled trial for the treatment of complex perianal fistulas in patients with Crohn’s disease indicated that both MSC apoptosis and PGE2production could be used as predictive biomarkers of MSC clinical efficacy.
These findings not only have important implications on stratifying patients for MSC therapy in different diseases, but also suggest that the induction of apoptosis independent of MSC therapy might occur during tissue injury to provide an anti-inflammatory and regenerative signal,and can represent an innate mechanism to promote tissue repair.
| Date of Award | 1 Oct 2020 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Francesco Dazzi (Supervisor) & Alberto Sanchez Fueyo (Supervisor) |