Ali, Sara Khalil Ebrahim; (2023) Characterisation of the human mesenchymal stromal compartment in normal homeostasis and acute myeloid leukaemia at the level of the single cell. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The bone marrow is a complex tissue comprising two distinct but interdependent compartments, namely the haematopoietic and “niche” compartments. In addition to providing structural support, the bone marrow microenvironment provides an array of instructive signals that are necessary for maintenance of normal hematopoietic function. Of the niche constituents, mesenchymal stromal cells (MSC) have emerged as a key player in both normal and malignant haematopoiesis. In acute myeloid leukaemia (AML), increasing evidence points towards dysregulation of MSCs and their role in promoting leukemogenesis and inhibiting normal haematopoiesis. However, studies to date have predominantly evaluated MSCs retrospectively, utilising culture-expanded MSCs which do not necessarily reflect the state of MSCs in their in situ milieu. Leveraging the combined powers of single cell RNA sequencing (scRNA-seq) and mass cytometry, we provide here an in-depth characterisation of the human bone marrow MSC compartment both in normal homeostasis and AML. Our findings shed light on the long-standing question of MSC heterogeneity, revealing MSC subsets of varying differentiation potential that exist along a continuum of cellular states. This pattern of cellular diversity is however lost in culture-expanded MSCs underscoring the limitations associated with their use. Comparison with scRNA-seq data of murine stroma shows a high degree of conservation in cellular architecture. Furthermore, our analysis of MSCs in the setting of AML reveals distinct transcriptional reprogramming including upregulation of the gene midkine (MDK) in AML-derived MSCs which appears, according to our preliminary findings, to play a role in maintaining HSC quiescence, thereby potentially contributing to the differentiation block seen in AML. In summary, our data reveal novels insights into the cellular architecture of the human MSC compartment in its native, unmanipulated state as well as unravel key transcriptional changes that characterise MSCs in AML, which can potentially be exploited for therapeutic targeting.

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