Characterising the wild mouse bone marrow: composition and cellular heterogeneity

  • Andrew Muir

Student thesis: Phd

Abstract

The murine bone marrow has a central role in both health and immune function as the primary source of leukocytes in adult mice. In addition to the production of leukocytes, the bone marrow is also a major modulator of immune function, as transcriptional changes in progenitor populations alter the phenotype of progenitor-derived leukocytes. Environment linked factors such as infection, diet and the microbiota are well studied modulators of bone marrow function, driving systemic changes in immune responses. In conjunction, laboratory mice provide a human-homologous, genetically manipulable, and reproducible model that has enabled an immeasurable volume of high-quality immunological research. However, the requirements to rear mice in laboratory conditions limits the potential for research into immune-environmental interactions. Moreover, recent research has questioned the translatability of laboratory mouse research into humans with some aspects of the wild mouse immune phenotype mirroring the human immune phenotype more closely than laboratory mice do. Given the importance of the bone marrow to systemic immune function and the known interactions between environmental factors and bone marrow function, investigating the wild mouse bone marrow presents an opportunity to study how the environment impacts on systemic immune function in a real-world setting. To date, there have been no studies providing an in-depth cellular analysis of the wild mouse bone marrow, as such the principal goal of this PhD project was to characterise the composition and phenotype of the wild mouse bone marrow and provide contrast with its laboratory mouse counterpart. This PhD project utilised wild Mus musculus domesticus from an isolated island population (Isle of May, Scotland, United Kingdom). As an island habitat with extremely limited human interactions, the Isle of May is ideal for studying the impacts of natural environmental variables on immunological, ecological and health based metrics. To provide contrast, C57BL/6 mice (the most commonly used laboratory strain) and ICR mice (a common outbred strain derived from CD-1) were chosen alongside a long-term life-cycle stress model using six month old, retired breeders that had been utilised as breeding stock since maturity. Alongside biometric and ecological assessment, bone marrow samples from each mouse were collected and characterised via flow cytometric and histological methods. Specifically, the composition and phenotype of B cells, CD4+ T cells, CD8+ T cells, eosinophils, neutrophils, monocytes, leukocyte progenitors and adipocytes were measured and analysed via several methodologies including principal component analysis, hierarchical clustering, and determination of mutual information. This project finds that, compared to laboratory mouse bone marrow, the wild mouse bone marrow differs in every cell type assessed. Some of the major distinctions include enrichment in plasma cells, increased KLRG1 expression by CD8+ T cells, diminished CD11b expression in the myeloid lineage and a five-fold enlargement of the eosinophil compartment. Furthermore, ecological features such as month and site of capture strongly associate with specific immunological phenotypes. This thesis thereby concludes that the wild mouse bone marrow is dramatically distinct from its laboratory mouse counterparts, with multiple phenotypes unique to the wild mouse that are tentatively linked to aspects of the wild mouse environment.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorIris Mair (Supervisor), Andrew Brass (Supervisor), Kathryn Else (Supervisor) & John Grainger (Supervisor)

Keywords

  • Immunology
  • Wild Mice
  • Ecology
  • Bone Marrow

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