Fibroblast heterogeneity in embryonic development and skin wound healing

Quan Minh Phan

doi:10.7273/000005125

The skin is a complex organ composed of multiple cell types, and its ability to regenerate and maintain physiological functions depends on the intricate interplay among these cells. The dermal fibroblast is the main cell type within the dermis layer and plays a critical role in skin development and regeneration. There is significant heterogeneity within the fibroblast populations, as there are multiple fibroblast lineages with distinct functions. Understanding the mechanisms regulating fibroblast heterogeneity and how different fibroblast lineages arise could have significant implications for maintaining and regenerating skin tissue. Chapter two of this dissertation investigates the establishment of distinct fibroblast lineages during embryonic development using a combination of single-cell multiomics, in vivo transgenic mouse models, and ex vivo allografting assays. The study found that dermal fibroblast progenitors (DFP) possess a repressed chromatin profile marked by the histone modification H3K27me3. As DFPs differentiate into distinct lineages, specific chromatinregions become accessible by the demethylase activity of Jmjd3. Tissue-specific deletion of Jmjd3 leads to the inhibition of two major skin structures: the dermal white adipocytes and the hair follicle-associated fibroblasts – the dermal papilla. Altogether, this study reveals the epigenetic mechanism regulating the differentiation process of DFPs and defines the distinct transcriptomic and chromatin states of different fibroblast lineages at different stages of development. In the next chapter, I investigate the differences between neonatal and adult skin that are responsible for the regenerative capacity of neonatal skin. This study identified a transient cell type called neonatal papillary fibroblast, which is defined by the expression of the canonical Wnt transcription factor Lef1. Tissue-specific knock-out of Lef1 revealed that Lef1 expression in neonatal fibroblasts is essential to hair follicle regeneration post-wounding. Overexpression of Lef1 in adult fibroblasts also reinstates neonatal regenerative ability. Additionally, in chapter three, I compared single-cell transcriptomics data from different skin regeneration models to identify a distinct upper wound fibroblast population, which shares a similar gene signature to the neonatal papillary fibroblast, is required for hair follicle regeneration. In conclusion, I have demonstrated that skin regeneration could be achieved by harnessing the regenerative capacity of distinct fibroblast populations. Overall, the works in this dissertation shed light on the mechanisms regulating fibroblast heterogeneity and how controlling the regenerative fibroblast population could improve skin wound healing. Our findings also highlight the therapeutic potential of fibroblast heterogeneity in regenerative medicine to restore and maintain tissue integrity.

Fibroblast heterogeneity in embryonic development and skin wound healing

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