Strange, Kathryn Emily; (2024) Identifying Donor Derived Differences in the Immunomodulatory Capacity of Umbilical Cord Mesenchymal Stromal Cells. Doctoral thesis (Ph.D), UCL (University College London).

Text KStrange_PhD.pdf - Accepted Version Access restricted to UCL open access staff until 1 February 2025. Download (77MB)

Abstract

Treatment options for haematopoietic malignancies includes total eradication of a patient’s own immune system, and replacement with donor haematopoietic stem and progenitor cells. However, a post-transplant complication is the activation of alloreactive donor cells against the patient, called graft versus host disease (GvHD), which can cause severe decline in quality of life and increase chance of mortality. Mesenchymal stromal cells (MSCs) have been utilised in clinical trials for the treatment of steroid resistant GvHD, among a range of other conditions due to their range of functions, such as immune regulation, regeneration, and wound healing. With their diverse activity comes complicated mechanisms of action, which have yet to be fully elucidated, and is one of the reasons for limited translatability post-clinical trial. Other reasons for limited clinical efficacy include the inter-trial variability in MSC source, donor, and preparation, leading to conflicting results. This project aimed to identify mechanisms of MSC functional potency through investigation of the secretome in general and specific secreted proteins, such as HLA-G. To achieve this, MSC isolation and culture from umbilical cord tissue was standardised to generate a pool of proliferative and potent MSCs. These were used as a base for identifying inherent variability, in particular due to the tissue donor. Through using an explant-based isolation methodology and expansion of MSCs from a range of umbilical cord donors, variability in immunosuppressive potency was identified. This was found to be attributable to variable secretion of diverse factors within the secretome, as well as differential post-translational modification of HLA-G isoforms. Using these results, novel mechanisms of MSC action have been elucidated, and biomarkers suggested for selection of more immunosuppressive MSCs. This will aid improvements in the reproducibility of MSC results in clinical trials, advance overall translatability, and increase the development of approved MSC-based therapeutic products.

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