Pedersen Wilson, Amy B.

Gentek, Rebecca

Kapoor, Simran

Wellcome Trust Host Pathogen and Global Health PhD studentship

Chancellor’s Fellowship from the University of Edinburgh

Senior Research Fellowship from the Kennedy Trust for Rheumatology Research

Cancer Research UK

2026-04-24T15:17:28Z

2026-04-24

Mast cells (MCs) are granulocytic immune cells classically recognised for their detrimental roles in allergic disease. Widely distributed throughout almost all tissues in the body, MCs are tissue-resident cells that release various mediators during allergic responses, driving pathological tissue remodelling. However, these same effector mechanisms may also participate in beneficial tissue remodelling during development and homeostasis. Emerging studies have proposed that MCs influence vascularisation and innervation processes which are re-shaped during allergy and anaphylaxis. Yet, whether they play a critical role in normal tissue development remain largely unexplored. Despite their early emergence during fetal development, the prevailing view is that MCs are dispensable for essential tissue development and organogenesis, largely based on observations from conventionally used MC-targeting mice models that appear phenotypically normally without overt developmental defects. However, it remains possible that these genetic models may not sufficiently ablate MCs at developmental windows where they play a critical function. Genetic MC-deficiencies have not yet been identified in humans, lending support to the controversial yet plausible hypothesis that MCs play a critical role in tissue development and survival, and therefore, remain strongly evolutionarily conserved. The aim of this thesis is to re-define the paradigm of the developmental significance of MCs in tissue development. Previously, conventional cKit-based MC-targeting models were used to report the critical developmental function of MCs for mammary gland morphogenesis during puberty. Using newly developed MC-targeting mouse models, I demonstrate that MCs are not critical for tissue development postnatally in the mammary gland at least, indicating that the previously used cKit-based approach may be unsuitable for evaluating MC function in this context. Investigating the critical functions of MCs during development therefore remains and requires a clear understanding of MC identity during development. To address this, I combined single cell RNA sequencing approaches to comprehensively characterise MC ontogeny as they emerge during embryonic days 15.5 to 18.5 in the fetal liver and peripheral tissues. This work revealed that MC developmental kinetics follow a conserved developmental programme, and tissue-specific cues shape the heterogeneity of MCs across tissues as they develop in situ, suggesting potentially important roles in organogenesis. Building on the early expression of Cpa3 in MCs as they develop during embryogenesis, we newly generated a Cre-based targeting model in which Cpa3-Cre driven diphtheria toxin expression in cells may enable direct disruption of MC development in utero to assess its developmental consequences. In contrast to previous assumptions, perturbation of MC development in this novel genetic approach resulted in severe neonatal lethality. This phenotype was associated with altered haematopoiesis and reduced platelets, impaired tissue development, and dysfunctional fetal lungs leading to respiratory distress in these mice shortly after birth. These findings demonstrated that early Cpa3-based disruption has profound consequences for developmental homeostasis. Collectively, this work introduces new genetic tools for developmental immunology in the field of MC biology and uncovers key insights into MC haematopoietic development and functions in organogenesis and tissue development.

https://era.ed.ac.uk/handle/1842/44592

https://doi.org/10.7488/era/7108

en

Kapoor, S. et al. (2025) “Mast Cells Are Not Essential for Pubertal Mammary Gland Branching,” European Journal of Immunology, 55(8), p. e70036. Available at: h ps://doi.org/10.1002/EJI.70036.

mast cells

mouse models

tissue development

genetic MC-deficiencies

MC-targeting mouse models

fetal liver

Cpa3

embryogenesis

MC haematopoie c development

Mast cell ontogeny and functions in tissue development

Thesis

Doctoral

PhD Doctor of Philosophy