Abstract
dc:description.abstractDevelopment of human connective tissue, termed ‘mesenchyme’, is a dispersed process in utero involving a diversity of cell lineages across organ systems. Diseases of these cell lineages, including fibroblasts and cartilage, affect numerous organ systems throughout human lifespan, manifesting as genetic, inflammatory, malignant and degenerative conditions. In turn, these contribute to a significant proportion of global disability burden, particularly through conditions of the developing and aging musculoskeletal system. The human developmental cell atlas consortium has begun to characterise these lineages transcriptionally in the early embryonic limb. However, there remains a paucity of studies applying emerging spatial and multiomic technologies to deeply map mesenchyme development in the human embryo in spatial and epigenetic contexts. Understanding the basis of cell fate decisions that drive the development of progenitors into numerous mesenchymal lineages can shed light on disease mechanisms. The underlying motivation of my thesis was therefore to address this recognised gap in knowledge. In this thesis I first applied paired single-cell RNA and ATAC sequencing, along with spatial transcriptomics to create an atlas of the cell states within the developing human appendicular and cranial skeleton in the first trimester. I then catalogued progenitors, as structures of the synovial joints emerge, and shed new light on the taxonomy of fibroblast and chondrocyte development. I proceeded to study signals involved in the development of joint diseases and reveal disease-specific enrichment in developmental cell states. Extending on this work, I study osteogenesis by examining the cells of the cranial sutures and limbs, revealing niches that contribute to cranial and appendicular bone formation. This enabled a first transcriptional characterisation of cranial bone cells and the cell states affected by congenital conditions of the human cranium. Lastly, I profiled the developing meninges, the mesenchyme layers that overlies the brain, across the first and second trimesters, exploring transcriptional links between fibroblast development and meningioma formation. I also studied meninges affected by trisomy 21, and explored altered cell types that underlie this condition. There were numerous biological insights derived from this work. For example, I gathered evidence of human cross-lineage chondrocyte development from Schwann cell progenitors and clarified stepwise organisation of fibroblast progenitors in the first trimester. I also uncovered cellular mechanisms of bone and meninges formation in the cranium across developmental time at single-cell resolution, contributing a data resource to the Human Cell Atlas and broader research community.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- To, Kendrick
- Advisor dc:contributor.advisor
-
- Teichmann, Sarah
Subjects
dc:subject × 1Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.121806
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/390151