Abstract
Mammalian skin is composed of two layers, the epidermis, and the underlying dermis. The main cell type within the dermis are fibroblasts which have distinct functions during skin development and regeneration. In mouse back skin fibroblasts arise from a common Pdgfrα+ progenitor and by E18.5 have formed distinct upper (papillary, Lrig1+) and lower (reticular, Dlk1+) lineages. Blood vessels are located throughout all layers of the dermis. The outermost layer of the blood vessel, the adventitia, is host to many different cell types including adventitial fibroblasts and pericytes. Pericytes can be distinguished from other perivascular cells due to their partial embedment within the basement membrane, their prominent nucleus, and long cytoplasmic processes which wrap around the vessel. Pericytes have been shown to express a range of different markers including Rgs5, Pdgfrβ, and Ng2 (Neural/glial antigen 2). Ng2 is the most widely used marker as it has been shown to consistently label pericytes in multiple organs across multiple types of vessels. Although pericytes have often been thought to be lineage-related to fibroblasts, the lineage relationship between specific fibroblast and pericyte populations within the skin remains to be properly explored.In this thesis we have investigated Ng2+ pericyte heterogeneity and their lineage relationship with fibroblast populations within skin development, wound healing, Bleomycin-induced skin fibrosis, and acute UV-B radiation mouse models. Utilising transgenic mice and lineage tracing technology we show papillary (Lrig1+), and reticular (Dlk1+) fibroblast populations give rise to Ng2+ pericyte populations whilst Ng2+ pericyte populations remain blood vessel resident during skin development and wound healing. Using Pdgfrα and β expression we found Ng2+ blood vessel resident pericytes in adult mice can be further subdivided into 4 populations, demonstrating unexpected levels of heterogeneity.
Within Bleomycin-induced fibrosis the total Ng2+ blood vessel resident pericyte population remains unchanged. However, Ng2+ Pdgfrα/β+ subpopulations significantly decrease whilst Ng2+ Pdgfr- pericytes significantly increase. Importantly, we also discovered a significant decrease in Pdgfrα+ fibroblasts in response to Bleomycin treatment which we propose is a result of apoptosis and macrophage facilitated phagocytosis.
During acute UV-B radiation mediated repair, Ng2+ Pdgfrα+ pericyte subpopulations decrease on blood vessels within the papillary dermis due to a decreased contribution of Lrig1+ papillary fibroblasts. Additionally, acute UV-B radiation results in a transient decrease in upper papillary fibroblasts due to apoptosis and proliferation respectively with minimal migration.
These findings have enhanced our knowledge of Ng2+ pericyte heterogeneity and their lineage relationship with fibroblast populations during skin development and within different models of repair.
| Date of Award | 1 Mar 2022 |
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| Original language | English |
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| Supervisor | Fiona Watt (Supervisor) & Jemima Mellerio (Supervisor) |